research articles about lipids

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• Biomol Ther (Seoul)
• v.29(6); 2021 Nov 1

Lipid Metabolism, Disorders and Therapeutic Drugs – Review

Vijayakumar natesan.

1 Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar 608002, Tamilnadu, India

Sung-Jin Kim

2 Department of Pharmacology and Toxicology, Metabolic Diseases Research Laboratory, School of Dentistry, Kyung Hee University, Seoul 02447, Republic of Korea

Different lifestyles have an impact on useful metabolic functions, causing disorders. Different lipids are involved in the metabolic functions that play various vital roles in the body, such as structural components, storage of energy, in signaling, as biomarkers, in energy metabolism, and as hormones. Inter-related disorders are caused when these functions are affected, like diabetes, cancer, infections, and inflammatory and neurodegenerative conditions in humans. During the Covid-19 period, there has been a lot of focus on the effects of metabolic disorders all over the world. Hence, this review collectively reports on research concerning metabolic disorders, mainly cardiovascular and diabetes mellitus. In addition, drug research in lipid metabolism disorders have also been considered. This review explores lipids, metabolism, lipid metabolism disorders, and drugs used for these disorders.

INTRODUCTION

Lipids are organic compounds that are insoluble in water and soluble in organic solvents. They are esters of fatty acids, rarely containing alcohol or phosphate functional group molecules, and comprise triglycerides, phospholipids, and steroids. They are the energy reserves of animals and perform various functions, such as maintenance of body temperature, whilst being the key constituents of cell membranes and serving as chemical messengers ( Tocher, 2003 ; Ratnayake and Galli, 2009 ). The human body requires various types of useful lipid fat to maintain the healthy functions of its parts ( Ahmed et al ., 2020 ). Balancing lipid levels in the blood is an important part of staying healthy. Abnormal levels of blood lipids cause fat deposits in artery walls, which initiates complications inside the blood vessels. Causes for high lipid levels include diabetes, alcoholism, kidney disease, hypothyroidism, liver disease, and stress. Augmented lipids easily adhere to the blood’s circulating nerve walls, and the growing fatty scale causes a variety of atherosclerosis disorders, such as stroke or heart attack ( Nelson, 2013 ).

A lack of chemical reactions in our bodies causes metabolic diseases and lowers our quality of life. The enzymes needed to metabolize lipids may not work properly or are not produced enough ( Lattimer and Haub, 2010 ). Excessive lipids are stored, causes permanent cellular and tissue damage, predominantly in the brain and peripheral nervous system, resulting in metabolic disorders such as Gaucher’s disease, Tay-Sachs disease, Niemann-Pick disease (NPD), etc. ( Solomon and Muro, 2017 ). Obesity is now a common metabolic disorder, involving an excessive amount of body fat. It increases the risk of other diseases and health problems, such as heart disease, diabetes, high blood pressure, and certain cancers. Altered intestinal microbiota may stimulate hepatic fat deposition, also causing obesity and other metabolic disorders ( Arslan, 2014 ; Song et al ., 2019 ). Almost half of all cardiovascular disease-related fatalities occur as a result of a metabolic imbalance ( Knopp, 1999 ). Obesity is a major cause of cardio metabolic risk factors such as elevated plasma glucose levels, atherogenic dyslipidemia, elevated blood pressure, and so on ( Grundy, 2009 ).

According to the Mayo Clinic, while certain metabolic abnormalities can be discovered by continuous screening tests at birth, the majority are diagnosed after the onset of symptoms in adulthood. For example, the population of gut microbiota microorganisms in the human digestive system that are involved in beneficial metabolic action is high. ( Dibaise et al ., 2008 ). However, obese metabolic disease is caused by pathophysiological interactions that result in aberrant negative metabolic activity ( Hur and Lee, 2015 ). Based on the child’s viewpoint and progress, this condition can be detected as early as childhood. Because of deficiencies in the diagnostic and screening processes ( Denisenko et al ., 2020 ), physicians and drug researchers have yet to identify the optimal therapy for metabolic diseases (Metbd). Metbd caused by chemical reactions begins with obesity and progresses via different illnesses, such as infertility, hypothyroidism, hypoactive sexual desire disorder, nonalcoholic steatohepatitis, testosterone replacement, vaginal atrophy, cancer, type I diabetes, and type II diabetes ( Pischon et al ., 2008 ). In recent years, lipid metabolism disease insulin resistance has become a frequent worldwide concern, which necessitates more medication research and diagnosis ( Lark et al ., 2012 ; Monnerie et al ., 2020 ). Obesity-related illnesses are being caused by the excessive intake of saturated fat lipids ( Cena and Calder, 2020 ). The absence of certain lipids, such as polyunsaturated lipids and phospholipids, causes inflammation and disrupts the glucose-insulin balance ( Novgorodtseva et al ., 2011 ; Glass and Olefsky, 2012 ). Furthermore, several studies have indicated that the contribution of lipoxin A4 lipid levels has an influence on periodontal disease, kwonlic syndrome, and other chronic issues ( Doğan et al ., 2019 ). According to the National Institute of Neurological Disorders and Stroke, the impact of excessive fat accumulation (lipids) is the source of many health concerns, such as tissue damage, and liver, brain, bone marrow, peripheral nervous system, and spleen disorders. The data in this investigation reveals a variety of problems caused by alterations in lipid metabolism. As a result, this study summarizes the different Metbd and current medication development reports.

LIPID TYPES AND STRUCTURES

Aqueous insoluble lipids are molecules with complex structures as a result of several biochemical transformations ( Fahy et al ., 2011 ). Because of the participation of different enzymes and biological substances, the process of lipidomics is important to comprehend ( Nilsson et al ., 2019 ). Lipids contain hydrocarbons, a diverse and ubiquitous group of compounds that are non-polar soluble in organic solvents. They have significant structural variety, based on their variable chain length, and have a mass of oxidative, reductive, substitutional, and ring-forming capability, also with sugar residues and other functional groups ( Fahy et al ., 2011 ). Based on this, lipids are divided into several types, including saturated and unsaturated fatty acids, waxes, glycerol phospholipids, sphingo lipids, and glycosphingo lipids ( Fahy et al ., 2005 ). Lipids are liquids or non-crystalline solids with colorless, tasteless, and odorless qualities, and are energy-rich organic compounds with no ionic charge. The acetyl, propenyl, and isoprene functional groups of the building components of lipids also serve as hormones. Polyunsaturated fatty acids carry out a signaling function and are responsible for membrane structure ( Cani et al ., 2008 ; Bazinet and Layé , 2014 ).

LIPID OR FATTY ACID SYNTHESIS

Lipids or fatty acids are important components of the human body and have multiple functions in both health and diseases. Different lipids are synthesized by our body, based on the functional area, and are produced by lipogenic tissues in the presence of cytosol ( Tracey et al ., 2018 ). Lipids or fatty acids are synthesized from acetyl-CoA and NADPH through the action of enzymes called fatty acid synthases. Seven replications of four-cycle reactions were observed by Tracey et al . (2018) with various fatty synthesis mechanisms ( Nelson, 2013 ). Except for some essential fatty acids, the human body is able to synthesize most of the required fatty acids directly from precursors ( Nagy and Tiuca, 2017 ). Acetyl-CoA carboxylase beta (ACC2) is involved in the carboxylation of acetyl-CoA to malonyl-CoA. Malonyl-CoA is the substrate for fatty acid synthase complex and is also a key molecule regulator of both the biosynthesis and oxidation of fatty acids ( Leśniak et al ., 2015 ; Alves-Bezerra and Cohen, 2017 ). The Coronavirus host protein has ACC2 and a chief lipid complex, which are arranged on the mitochondrial membrane ( Castle et al ., 2009 ). Long chain fatty acid synthesis is found in all cells and organisms, serving as the universal building block of sphingolipids, glycerophospholipids, triacylglycerols, and wax-esters ( Uttaro, 2006 ). Similarly, three fatty acid biosynthetic pathways were observed in different parts of Toxoplasma ( Coppens et al ., 2014 ). From the results, this review observed the importance of lipid synthesis in various organisms and pathways.

LIPID FUNCTIONS AND ITS METABOLISM

Lipid metabolism is involved in different active functions of our body, such as energy storage, hormone regulation, nerve impulse transmission, and fat-soluble nutrient transportation. Lipids serves as an energy source with high caloric density, providing 9 kcal of energy when compared to protein and carbohydrates, which can also store 100,000 kcal of energy in our body functions without any intake of food for 30-40 days, only requiring sufficient water ( Ophardt, 2003 ). Biochemical lipids are stowed in cells all over the body, in specific varieties of connective tissue, named adipose. Lipids protect human organs, such as the spleen, liver, heart, and kidneys, from damage ( Church et al ., 2012 ).

Lipids that exist in the blood are absorbed through liver cells and provide the correct concentrations to various parts of the body. The liver plays a key and vital role in lipid metabolism ( Ophardt, 2003 ). The liver serves as a substitute reservoir for storing extensive quantities of excess fat. Through prolonged energy overload, the unspent excess energy is stored in adipose tissue and in hepatocytes in the form of triglycerides ( Huang et al ., 2011 ). The metabolism cycle is extended to the citric acid cycle, the urea cycle, and the citric cycle ( Arumugam and Natesan, 2017 ).

Fatty acids are degraded via oxidation, which releases large amounts of ATP and produces sensitive oxygen ( Rosca et al ., 2012 ). The glycerolipids biosynthesized through snglycerol-3-phosphate dominate in the liver and adipose tissue ( Athenstaedt and Daum, 2006 ). This review observed various useful metabolic functions of proteins enabling an understanding of metabolic disorders ( Huang and Freter, 2015 ; Trebatická et al ., 2017 ; Musso et al ., 2018 ; Yan and Horng, 2020 ).

LIPID METABOLISM DISORDERS

Increasing or decreasing levels of lipids cause various health effects in the human body, which are called disorders. These types of disorders usually increase triglyceride, LDL, or both lipid levels. The body requires the useful fatty acid HDL, which helps to transport bad cholesterol out of the body. Similarly, the accumulation of bad and unwanted lipids, such as fatty LDLs and triglyceride, damage the arteries and have serious consequences for cardiovascular health. Recently, Xiao et al . (2021) published an article on inherited complex lipid metabolism disorders, stating that over 80 diseases have been identified as complex lipid metabolism defects. They reviewed the physiological role of lipid metabolism in health disorders, which defines various metabolisms, such as nonlysosomal sphingolipids, acylceramides, etc. Lipid metabolism-based disorders were classified into five types by Fredrickson’s, based on the pathway and health effects ( Quispe et al ., 2019 ). When compared to a lower level of lipids, a higher amount of lipid accumulation in the body causes more health disorders, which is known as hyperlipidemia ( Natesan and Kim, 2021 ). Hyperlipidemia refers to a group of serious lipid disorders caused by an abnormally high level of unwanted lipids in the blood ( Verma, 2017 ). The Verma’s review classified hyperlipidemia based on the lipid type ( Fig. 1 ) ( Verma, 2017 ). Verma (2017) reviewed Fredrickson’s familial disorders classifications, symptoms, and treatments for each kind of disorder (Fredrickson and Lee, 1965).

Classifications of lipid metabolism disorders based on the nature of lipid and factors.

The discrete lipid metabolic disorders classification varies based on concentrations of classes of lipoproteins, and several disorders are now observable with structural defects in the presence or absence of apolipoproteins and lipid transfer proteins, respectively ( Schonfeld, 1990 ).

The peroxisome proliferator-activated receptors are a type of lipid, which are also called nuclear fatty acid receptors, that have been associated with playing a vital role in obesity connected to metabolic diseases like coronary artery disease, hyperlipidemia, and insulin resistance ( Azhar, 2010 ). The peroxisome proliferator-activated receptors involving regulated pathways that control various lipid disorders were also reported for medical treatment purposes ( Lee et al ., 2003 ). In addition, various lipid metabolism disorders, such as bone related disorders, osteoporosis, and atherosclerosis, are major worldwide health problems for postmenopausal females ( Bagger et al ., 2006 ). The hypothetical evidence proposes a relationship between lipid metabolism and bone, which are mutually regulated ( Tian and Yu, 2015 ); however, some conflicting results were observed, which require some Chinese human subjects. Myopathy and the severity of carnitine deficiency are caused by the excessive accumulation of lipid droplets on muscle fibers ( Di Mauro et al ., 1980 ). Metabolic systems of lipids or lipid abnormalities cause various disorders and diseases. Furthermore, excess lipid storage in the body causes a variety of disorders, including xanthoma, Bassen-Kornzweig syndrome, methylmalonic acid blood test, chylomicronemia syndrome, familial lipoprotein lipase deficiency, Niemann-Pick disease (NPD type-A and NPD type-B), methylmalonic academia, GM1 & GM2 gangliosidoses, Gaucher disease, Aside from these, the more serious consequences are cardiovascular disorders and diabetes, both of which had no symptoms at the time. Nowadays, these are the major health issues in the digital world. The most common causes of acquired hyperlipidemia are diabetes mellitus, alcohol consumption, hypothyroidism, renal failure, nephrotic syndrome, and continuous use of diuretics, estrogens, and β-blockers ( Stone, 1994 ; Reckless and Lawrence, 2003 ).

CLASSIFICATION OF LIPID METABOLISM DISORDERS

The best way of classifying lipid metabolism disorders is descriptively ( Table 1 ), based on the changes in concentration of the various types of lipids. LDL hypercholesterolemia is distinguished from mixed hyperlipoproteinemia, hypertriglyceridemia, and an isolated reduction in HDL cholesterol. All of these lipid metabolism disorders can be associated with elevated lipoprotein(a). The treatment of the individual lipid metabolism disorders is described below.

Descriptive classification of the dyslipoproteinemias

EXCLUSION OF SECONDARY LIPID METABOLISM DISORDERS

Secondary lipid metabolism abnormalities can cause a variety of illnesses. Diabetes mellitus, hypothyroidism (LDL hypercholesterolemia), renal illnesses (hypertriglyceridemia, mixed hyperlipoproteinemia, lipoprotein elevation), and cholestatic liver disorders are the most common clinically. Lipid metabolism disorders have also been found in the setting of other illnesses (e.g., lymphoma, Cushing syndrome, and porphyria). When the lipid metabolism problem is a secondary manifestation, the primary emphasis of treatment should be on the underlying illness. People with chronic diabetes or renal illness are frequently outliers to this rule, because adequate control or eradication of the underlying disease is not accomplished, and they exhibit symptoms of both primary and secondary lipid metabolism problems.

LIFESTYLE MODIFICATION

Lifestyle changes are important in the treatment of lipid metabolism problems. Regardless of the treatments used, the decrease in high LDL cholesterol concentrations seldom exceeds 10% ( Malhotra et al ., 2014 ). The biggest impact is obtained by reducing the consumption of saturated fatty acids, namely animal fats. Because the influence of orally ingested cholesterol is small, the current recommendations in the United States do not advise limiting cholesterol consumption at all. Lifestyle modifications, alone or in conjunction with changes in lipid concentrations, have a significantly larger effect on hypertriglyceridemia. Severe limits on alcohol consumption and a reduction in the intake of quickly absorbed carbohydrates can reduce triglyceride levels by more than 50% ( Hegele et al ., 2014 ). Regular exercise also increases the lipid profile. Even if the effect on lipid concentration is modest in certain situations, lifestyle changes might have a positive influence on the risk profile. In high-risk individuals, for example, a Mediterranean diet supplemented with extra olive oil or almonds results in a 30% reduction in relative risk ( Estruch et al ., 2013 ). Surprisingly, consuming nuts lowers LDL cholesterol; thus, it is debatable that at least some of the risk reduction is due to a beneficial impact on the lipid profile ( Wu et al ., 2014 ).

LDL HYPERCHOLESTEROLEMIA

According to European recommendations, the target concentration of LDL cholesterol should be determined by the total risk. If lifestyle changes alone are insufficient to achieve this aim, statin medication is the initial step in medical therapy. If the goal LDL cholesterol level is not reached after 4 to 6 weeks of therapy, the dose should be modified. In high-risk individuals, both lifestyle changes and statin therapy should begin at the same time ( Catapano et al ., 2011 ). According to the results of the IMPROVE-IT trial, ezetimibe should be administered if statin therapy alone fails to attain the target LDL cholesterol concentration. If the combination of a statin and ezetimibe is still ineffective, PCSK9 antibodies might be used. Patients with atherosclerosis and resistant LDL hypercholesterolemia might be treated with frequent lipid apheresis as a last option.

In Germany, other statins (lovastatin, fluvastatin, pravastatin, rosuvastatin, pitavastatin) play a limited role. Fluvastatin and pravastatin have lower side effect rates than atorvastatin and simvastatin; thus, they can be used in individuals who cannot take the latter ( Stroes et al ., 2015 ). Rosuvastatin has a very potent LDL cholesterol-lowering effect; however, patients in Germany must bear a portion of the expenditure. Acute coronary syndrome (ACS) is a unique condition. Initial research indicates that extremely early high-dose statin treatment improves the prognosis of ACS patients ( Cannon et al ., 2004 ). The most probable reason is that LDL cholesterol has no effect on endothelial function ( Sparrow et al ., 2001 ). In the meantime, however, these findings are being viewed with caution. Nonetheless, most recommendations suggest that patients with ACS begin therapy with a high-dose statin.

MIXED HYPERLIPOPROTEINEMIA

Because of its strong connection with metabolic syndrome, mixed hyperlipoproteinemia, characterized by elevated levels of both LDL cholesterol and triglycerides, is the most common lipid metabolism disease in diabetics ( Wu and Parhofer, 2014 ). In this case, too, the primary therapeutic objective is to keep LDL cholesterol levels in check. The essential measure in the treatment of hypertriglyceridemia is a change in the patient’s lifestyle. If the combination of lifestyle changes and statin medication does not achieve the desired concentrations, or at least normalize the triglyceride level, combined medical treatment may be explored ( Hegele et al ., 2014 ). In theory, statins can be used with omega-3 fatty acids or fibrates, although both of these combinations have performed poorly in endpoint trials ( Kromhout et al ., 2010 ). However, due to the poor design of these trials, no conclusive result can be drawn, as each of these two classes of drugs decreased cardiovascular risk in monotherapy studies ( Chaudhury et al ., 2017 ). In our facility, patients with very high risk and a combined lipid metabolic problem are treated with statin + fibrate or statin + omega-3 fatty acids after all other LDL cholesterol-lowering options have been exhausted. Without comparative research, neither of these two therapies can be favored over the other. It may be advisable to test both combinations and then stick with the one that is best tolerated and produces the greatest results.

HYPERTRIGLYCERIDEMIA

Triglyceride levels are frequently much higher than normal in isolated hypertriglyceridemia, whereas LDL cholesterol levels are modest. Total cholesterol levels might be high. Isolated hypertriglyceridemia, like mixed hyperlipoproteinemia, typically responds favorably to lifestyle changes. Moreover, there is no way to predict whether a specific patient will react well or poorly. Because no compelling studies have been published, there is no agreement on when medical therapy should begin ( Yuan et al ., 2007 ). However, the threshold is lower among people at high risk of atherosclerosis than when hypertriglyceridemia is detected accidentally in an otherwise healthy person. A fibrate can be administered if the triglyceride level remains above 400 mg/dL (4.6 mmol/L), after the application of lifestyle modification strategies. Fenofibrate and gemfibrozil appear to be the best alternatives. Alternatively, omega-3 fatty acids can be administered alone or in combination, as necessary ( Hegele et al ., 2014 ). Statins are typically ineffective in isolated hypertriglyceridemia since LDL cholesterol is frequently already extremely low at the start. Patients with known atherosclerosis should get a modest dosage of statin regardless of LDL cholesterol levels.

There is general agreement that if the triglyceride level stays above 400 mg/dL (4.6 mmol/L) despite implementation of lifestyle modification measures, a fibrate can be given. The best options seem to be fenofibrate or gemfibrozil (positive endpoint studies; should not be combined with statins). Alternatively, omega-3 fatty acids can be given, in combination if indicated ( Hegele et al ., 2014 ). Statins are generally of little use in isolated hypertriglyceridemia, because the LDL cholesterol is often already very low at the outset. Clients with known atherosclerosis should be given a modest dose of statins, regardless of LDL cholesterol levels.

SYMPTOMS OF HYPERLIPIDEMIA

In general, hyperlipidemia disorders do not have any noticeable symptoms, but they are regularly exposed by the health monitoring process or by routine examination and will cause a stroke or a heart attack if it reaches a dangerous stage. Patients with more than the maximum cholesterol level in the blood will be affected by xanthomas. In this disorder, cholesterol deposits itself under the skin and in the eyes ( Shattat, 2014 ). A raised level of triglycerides was reported at the same time, causing numerous pimples in diverse sites of the patients’ bodies. Familial hypercholesterolemia is a common autosomal-related disorder caused by elevated LDL cholesterol levels at birth. It also causes premature coronary artery disease and requires initial diagnosis to avoid expensive generic pharmacotherapy ( McGowan et al ., 2019 ).

CARDIOVASCULAR DISORDER OR DISEASE (CVD)

According to healthcare providers, the well-established stage of lipids in the body causes risk factors for CVD, and the analysis of lipid-screening test results plays a critical role in CVD risk assessment. The Framingham Risk Score is the most widely used authenticated lipid-screening technique ( Nelson, 2013 ). CVD, or coronary heart disease, causes serious health issues, such as heart attack, heart failure, and stroke ( Joynt et al ., 2003 ). CVD is caused by chronic inflammatory atherosclerosis, which develops gradually in the human body over several years. The CVD risk factor dyslipidemia is related to lipid metabolism and is affected by genes and proteins. Computed tomography investigations on various lipid molecules, such as cholesteryl ester transfer protein, lipoprotein lipase, polymorphisms of paraoxonase 1 and 2, and hepatic lipase, were used to measure the relationship between CVD and lipid metabolism. The Diabetes Heart Study included 620 European American volunteers, with 83% having type 2 diabetes mellitus. The results revealed that the Q192R variant of paraoxonase 1 and rs285 of lipoprotein lipase were linked with carotid artery calcium ( p =0.002 and 0.005, respectively) and paraoxonase-2 S311C was connected with coronary artery calcium ( p =0.037), which was proven by Burdon et al . (2005) . Goldberg et al . (2012) reported the lipid metabolism effect on the heart, observing that excess lipid accumulation causes severe chest pain by obstructing blood flow, reducing oxygen flow and resulting in a heart attack.

CVD kills one out of every three women. Sex-specific data concentrated on cardiovascular disease has been growing steadily. The average lifetime is reduced due to CVD in women who are at an age of approximately 50 years (≈40%). However, significant causes of CVD are depicted in Fig. 2 ( Garcia et al ., 2016 ).

Various reasons for cardiovascular disorders by lipids storage related metabolic actions.

DIABETES MELLITUS

Diabetes mellitus is another disorder caused by lipid metabolism that necessitates a continuous health monitoring strategy for long-term survival ( Amalan and Vijayakumar, 2015 ). The impact of insulin on lipid metabolism, which is influenced by diabetes, may be measured in four different ways ( Saudek and Eder, 1979 ). The proposed mechanism exposed the negative and positive effect on insulin in the regulation of triglyceride metabolism.

Lipid metabolism is altered and changes are observed during Gestational Diabetes Mellitus and the normal pregnancy period. Hepatic and adipose metabolism alters the concentrations of triacylglycerols, cholesterol, phospholipids, and fatty acids ( Amalan et al ., 2015 ). Then, in the first 8 weeks of pregnancy, there is a preliminary decrease, followed by a gradual increase in the majority of the fatty acid or lipid concentrations. At the same time, the higher concentrations of estrogen and insulin resistance are believed to be accountable for the hypertriglyceridemia of pregnancy ( Butte, 2000 ). Their research on pregnant women with GDM has revealed that diet control and exercise have managed their diabetes.

Diabetic dyslipidemia is a collection of many irregularities in fat, both LDL and HDL intolerance levels. This pattern of lipoprotein deviations is extremely atherogenic and is associated with a rise in plasma triglyceride levels. The clinical irregularities take place at a range of plasma triglyceride levels, which represent the upper normal range or mild hypertriglyceridemia (>1.5 mmol/L). In clinical practice, this means that triglyceride levels should be maintained as low as possible in non-insulin dependent diabetes mellitus patients ( Taskinen et al ., 1996 ).

An experimental report on the regulation of lipids with glucose metabolism in the post absorptive and postprandial conditions in six subjects (selective patients or volunteers) with insulin-treated diabetes mellitus, matched with eight non-diabetic volunteers or subjects, involved the investigation of blood or plasma concentrations of metabolites and fluxes across forearm and subcutaneous adipose tissue after an overnight fast and for 6 hours after a mixed meal (3.1 MJ, 41% from fat). The observation revealed that the wider spread of plasma (free) insulin concentrations in the diabetic group led to a wider range of plasma non-esterified fatty acid release from adipose tissue, plasma NEFA concentrations, and blood ketone body concentrations ( Frayn et al ., 1993 ). These studies and reviews have confirmed lipid metabolism and its impact on health issues in different ways.

CONTROL AND TREATMENT METHODS

These kinds of lipid-based disorders can be controlled by various methods, such as physical methods, a controlled food system, therapeutic lifestyle changes, drug therapy, and proper health checkups ( Fig. 3 ). Statins are the most potent class of medicine used for cardiovascular diseases. Being cholesterol-lowering drugs, statins are expected to ameliorate the cardiovascular problem, which lowers the acute-phase proteins ( Pahan, 2006 ). Table 2 shows some anti-lipidemia drugs, as well as their mechanisms and side effects ( Waller and Waller, 2014 ; Dias et al ., 2018 ).

Methods of controlling lipid disorder.

Anti-lipidemia drugs and their mechanism with side effects

This shows a list of anti-lipidemia drugs and their mechanism in fat or cholesterol control at different parts of body using different metabolic chemicals along with drugs side effects.

CONTROL OF SATURATED VS. UNSATURATED FATTY ACIDS (FAS)

The amounts of saturated FAs incorporated in cell membrane phospholipids change, depending on the source of FAs, de novo lipogenesis, or external lipid absorption. The lipogenic process raises the saturation level of cell membranes with saturated and monounsaturated fatty acids (MUFAs) ( Yue et al ., 2014 ; Fernandez et al ., 2020 ), which are less susceptible to lipid peroxidation than the polyunsaturated acyl chains (PUFAs) acquired mostly via food. In this approach, de novo lipogenesis helps to make cancer cells resilient to oxidative stress and chemotherapy ( Rysman et al ., 2010 ).

Nonetheless, an excess of saturated FAs in cell membranes might cause lipotoxicity. In this context, SCD1 inhibition promotes endoplasmic reticulum (ER) stress and death in cancer cells and reduces tumor development in colon and lung cancer xenograft models. The core regions of tumors are subjected to hypoxia and decreased nutritional availability during tumor development. Tumors have evolved several techniques for balancing the amounts of saturated vs. unsaturated FAs and anticipate lipotoxicity by increasing MUFA/PUFA absorption from plasma, which is then stored in lipid droplets (LDs) or integrated into phospholipids at the cell membranes. Because SCD1 activity requires oxygen, certain cancers rely on the activity of diglyceride acyltransferase (DGAT) during hypoxia to integrate MUFAs into triglyceride (TG), which is then deposited into LDs ( Fernandez et al ., 2020 ). Furthermore, cancers regulate the amounts of saturated vs. unsaturated FAs in phospholipids at the cell membranes via the Lands cycle. Recently, a mechanism known as ferroptosis has been identified, which is related with high amounts of MUFA/PUFAs in cell membrane phospholipids, causing cell death by oxidation via the Fenton pathway. Long-chain FA acyl CoA synthetases (ACSLs), which are involved in long chain FA activation, may regulate ferroptosis, because different isoforms employ different substrates. Conversely, although ACSL4’s major substrates are PUFAS, such as AA, ACSL3 may activate both MUFAs and PUFAs, allowing for better regulation of PUFA buildup in phospholipids ( Alwarawrah et al ., 2016 ). Furthermore, ACSL3 provides for better regulation of FA distribution between LD storage and fatty acid oxidation (FAO), allowing for better management of oxidative stress.

CURRENT TREATMENT MODALITIES

A variety of novel methods for the treatment of lipid metabolism diseases have been explored. Proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies are particularly significant ( Stein et al ., 2013 ). Even in individuals who have previously had combination statin and ezetimibe treatment, these medicines can result in a 50 to 60% decrease in LDL cholesterol ( Blom et al ., 2014 ). PCSK9 antibodies have just a little effect on triglyceride and HDL cholesterol concentrations. They do, however, reduce lipoprotein(a) levels by up to 30% ( Raal et al ., 2014 ; Parhofer, 2016 ). Until the endpoint comprehensive research is completed and published, PCSK9 antibodies can only be given to carefully selected patients, such as those with known atherosclerosis and prominent LDL hypercholesterolemia who cannot be treated by other means due to their levels being too high or who are unaware of statins.

Hyperlipidemia, a major cause of coronary heart disease, diabetes, and cancer, is prevalent throughout the world. Numerous studies and reviews have been reported on metabolism, the causes of lipid-based disorders, and the effects of fatty acids. Despite the fact that many drugs are available on the market, society continues to face problems as a result of CVD. To minimize the risk of cardiovascular related heart failure, heart attacks due to hyperlipidemia need novel drugs that can decrease lipids such as cholesterol and triglycerides in the blood. This review mainly focuses on compiling reports on lipids, metabolism, CVD, and diabetes related issues. Still, there is no complete report on lipid metabolism disorders and drug discovery. As a result, this review has been launched with only the most basic reports for further investigation.

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Novel Insights into the Modulation of Protein Function by Lipids and Membrane Organization

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A continuously growing amount of evidence underlines the active contribution of lipids and membrane organization to the regulation of the structure and function of transmembrane proteins. In general, lipids of the cell membrane can affect proteins through a mixture of direct and indirect mechanisms. While the ...

Keywords : protein function, lipids, membrane organization

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• Published: 27 March 2024

The serum soluble ASGR1 concentration is elevated in patients with coronary artery disease and is associated with inflammatory markers

• Qin Luo 1 , 2 ,
• Jingfei Chen 3 ,
• Yanfeng Yi 1 , 2 ,
• Panyun Wu 1 , 2 ,
• Yingjie Su 4 ,
• Zhangling Chen 1 , 2 ,
• Hacı Ahmet Aydemir 5 ,
• Jianjun Tang 1 , 2 ,
• Zhenfei Fang 1 , 2 &
• Fei Luo 1 , 2  

Lipids in Health and Disease volume  23 , Article number:  89 ( 2024 ) Cite this article

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Background and aims

Current research has suggested that asialoglycoprotein receptor 1 (ASGR1) is involved in cholesterol metabolism and is also related to systemic inflammation. This study aimed to assess the correlation between the serum soluble ASGR1 (sASGR1) concentration and inflammatory marker levels. Moreover, the second objective of the study was to assess the association between sASGR1 levels and the presence of coronary artery disease (CAD).

The study subjects included 160 patients who underwent coronary angiography. Ninety patients were diagnosed with CAD, while seventy age- and sex-matched non-CAD patients served as controls. We measured the serum sASGR1 levels using an ELISA kit after collecting clinical baseline characteristics.

Patients with CAD had higher serum sASGR1 levels than non-CAD patients did ( P  < 0.0001). sASGR1 was independently correlated with the risk of CAD after adjusting for confounding variables (OR = 1.522, P  = 0.012). The receiver operating characteristic (ROC) curve showed that sASGR1 had a larger area under the curve (AUC) than did the conventional biomarkers apolipoprotein B (APO-B) and low-density lipoprotein cholesterol (LDL-C). In addition, multivariate linear regression models revealed that sASGR1 is independently and positively correlated with high-sensitivity C-reactive protein (CRP) ( β  = 0.86, P  < 0.001) and WBC ( β  = 0.13, P  = 0.004) counts even after adjusting for lipid parameters. According to our subgroup analysis, this relationship existed only for CAD patients.

Our research demonstrated the link between CAD and sASGR1 levels, suggesting that sASGR1 may be an independent risk factor for CAD. In addition, this study provides a reference for revealing the potential role of sASGR1 in the inflammation of atherosclerosis.

Introduction

Atherosclerotic cardiovascular disease (ASCVD) is a fatal disease with a complex etiology worldwide. Over the last few decades, there has been constant updating and even subversion of the understanding of atherosclerosis [ 1 ]. In parallel, an increasing number of atherosclerotic markers have been discovered [ 2 , 3 ]. Disorders of lipid metabolism, especially hypercholesterolemia, are well-known pathogenic risk factors for ASCVD [ 4 ]. Lipoproteins are the initial points of interest. Oxidized low-density lipoprotein (ox-LDL) or small dense LDL enters the artery wall, which constitutes the classic early stage of atherosclerosis [ 2 , 5 ]. Of course, circulating adhesion molecules such as vascular cell adhesion molecule-1 (VCAM), intercellular adhesion molecule-1 (ICAM), and monocyte chemotactic protein-1 (MCP-1) play crucial roles in this stage [ 5 , 6 ]. High triglyceride (TG) and residual cholesterol levels are important pathogenic factors of ASCVD and were recognized when residual cardiovascular risk associated with statins was discovered [ 7 , 8 ]. Other lipoproteins, such as lipoprotein(a) [Lp(a)] and apolipoprotein B (APO-B), have also been found to be associated with the risk of atherosclerosis [ 5 ]. Evaluating the characteristics of coronary artery plaques using the latest invasive or noninvasive imaging methods can help predict the risk of cardiac events and guide personalized treatment strategies [ 9 , 10 , 11 ]. A higher plaque burden and high risk plaques are independent risk factors for myocardial ischemia [ 11 , 12 , 13 ]. In addition, recent studies have established that inflammatory markers participate in all stages of atherosclerosis, making them one of the most promising therapeutic targets for treating this disease [ 14 , 15 ].

Asialoglycoprotein receptor (ASGR) is a hepatic C-type lectin that is expressed mainly on the sinusoidal surface of hepatocytes [ 16 , 17 ]. The primary function of ASGR is to bind glycoproteins containing terminal galactose or GlcNAc residues (such as asialoglycoproteins) in circulation [ 18 , 19 ]. The complex is subsequently internalized under the coat of clathrin and transported to the lysosome for degradation [ 20 ]. As a hepatocyte membrane receptor, asialoglycoprotein receptor 1 (ASGR1) regulates hepatic cholesterol homeostasis by interacting with circulating asialoglycoproteins [ 21 ]. In animal studies, inhibiting hepatic ASGR1 or its binding to circulating asialoglycoproteins reduces serum cholesterol levels by promoting cholesterol efflux into the bile [ 21 ]. ASGR1 loss-of-function mutations are linked to a 0.4 mmol/l decrease in circulating non-high-density lipoprotein cholesterol (non-HDL-C) and a 34% reduction in the incidence of coronary artery disease (CAD) [ 22 ]. Notably, the effect of the ASGR1 mutation on the risk of CAD is significantly greater than that on non-HDL-C levels, suggesting that the significant reduction in the risk of CAD is not entirely explained by the effect of ASGR1 mutations on non-HDL-C levels [ 22 , 23 ]. Therefore, ASGR1 mutations may be involved in other protective mechanisms than the regulation of cholesterol homeostasis, such as inflammation. Indeed, some direct or indirect evidence has shown that ASGR1 is involved in biological processes related to systemic inflammation and vascular inflammation [ 24 , 25 , 26 , 27 ]. For example, proinflammatory cytokines upregulate the expression of ASGR1 [ 24 ]. The interaction of ASGR1 with epidermal growth factor receptor (EGFR) activates the extracellular signal-regulated kinase (ERK) pathway [ 25 ], which has been linked to inflammatory regulation and atherosclerosis [ 28 , 29 ]. However, the relationship between ASGR1 and inflammation in patients with CAD is unclear.

In contrast to ASGR1, which is located on the liver surface mentioned above, serum soluble ASGR1 (sASGR1), which is secreted by the liver, is another splicing variant of liver ASGR1 and is located in the circulation due to the absence of a transmembrane domain [ 30 ]. However, current research on sASGR1 is very limited. Although our previous study showed that sASGR1 is associated with LDL-C levels [ 31 ], the relationship between sASGR1 levels and the risk of CAD is still unclear.

C-reactive protein (CRP) levels and white blood cell (WBC) counts are the most basic and widely used indicators of systemic inflammation. In addition, CRP levels are positively correlated with the degree of coronary artery stenosis in patients with CAD [ 32 ]. Two recent studies have established that high-sensitivity C-reactive protein (hs-CRP) levels exhibit superior predictive power for future cardiovascular events and mortality risk when compared to circulating cholesterol levels in patients receiving statin therapy [ 33 , 34 ]. Similarly, WBC counts have been widely confirmed to be closely related to atherosclerosis and CAD [ 35 , 36 , 37 ]. Currently, there are no simple or effective methods for determining the level of ASGR1 expression on the hepatocyte membrane in clinical practice. Therefore, the purpose of this study was to assess the correlation between sASGR1 levels and inflammatory marker levels, including hs-CRP levels, WBC counts, and WBC subsets. Moreover, the second objective of the study was to assess the association between sASGR1 levels and the presence of CAD.

Materials and methods

Study population.

We consecutively included 160 patients admitted to the Second Xiangya Hospital of Central South University between September 2022 and September 2023 in this study. All patients underwent coronary angiography. Patients were categorized into two groups based on the results of coronary angiography: 90 patients with CAD and 70 patients without CAD. We matched the groups for age and sex. Four experienced angiographers performed coronary angiography, two of whom evaluated the vessels. To determine the severity of CAD, CAD patients were further subdivided into acute myocardial infarction (AMI) ( n  = 26) and CAD without AMI ( n  = 64) groups. The severity of coronary lesions was determined by the number of major coronary artery stenoses, which were classified as vessels ≤ 2 ( n  = 51) or vessels > 2 ( n  = 39). Furthermore, the Gensini score was also calculated to assess the severity of CAD. We excluded patients with infections, autoimmune diseases, liver diseases, renal failure, malignancies, or other serious diseases.

The diagnosis of CAD was based on angina pectoris manifestations, electrocardiogram changes, and coronary angiography, which indicated that the major vessel had a degree of stenosis greater than or equal to 50%. Elevated plasma troponin levels, together with evidence of acute myocardial ischemia, are diagnostic criteria for AMI [ 38 ]. Fasting blood glucose levels ≥ 126 mg/dl (7.0 mmol/L) or 2-hour postprandial blood glucose levels ≥ 200 mg/dL (11.1 mmol/L) were used to diagnose type 2 diabetes mellitus (T2DM). Repeated measures of blood pressure greater than or equal to 140/90 mmHg were used to diagnose hypertension.

The study was authorized by the ethics committee of Second Xiangya Hospital, which also found that it adhered to the ethical principles of the Declaration of Helsinki. Informed permission was obtained from all patients.

Sample size calculation

In the study assessing the association between sASGR1 levels and the presence of coronary artery disease (CAD), we used Power Analysis and Sample Size (PASS) software for sample size calculations. We set bilateral α = 0.05 and power = 0.9. The ratio of the sample size between the CAD group and the control group was 1.28:1. We set the mean and standard deviation of the sASGR1 levels for the two groups based on our preliminary results. The sample size calculation revealed that a sample of 55 CAD patients and 43 non-CAD patients achieved 90.31% power to reject the null hypothesis of equal means when the population mean difference was µ1- µ2 = 4–2.1 = 1.9 with standard deviations of 4 for the CAD group and 1.3 for the non-CAD group. Ultimately, 90 CAD patients and 70 non-CAD patients composed the sample.

Clinical characteristics and laboratory measurements

Basic information, including age, sex, body mass index (BMI), smoking status, and statin use, was collected and recorded. Peripheral blood samples were collected from patients through the elbow vein after they had fasted overnight. The serum was collected after centrifuging the blood sample for 10 min at 3,000 rpm and subsequently stored at -80 °C. Serum lipid parameters and hs-CRP levels were measured using a fully automated biochemical analyzer. WBCs, neutrophils, lymphocytes, and monocytes were counted using an automatic blood cell counter.

ELISA for determining the sASGR1 concentration

The serum concentration of sASGR1 was determined using sandwich enzyme-linked immunosorbent assay (ELISA) kits (JL41965; Jianglai Biology, Shanghai). Two measurements were repeated per sample to reduce random variations. Both the intraplate and interplate coefficients of variation (CVs) were less than 10%, suggesting that the assay has good repeatability. The recovery rate and linearity of this reagent kit were 95% and 91%, respectively (with a dilution ratio of 1:2). The minimum detectable concentration of serum sASGR1 was 0.156 ng/mL.

Statistical analyses

For the data analysis, we employed SPSS 25.0 statistical software. In addition, EmpowerStats statistical software (version 4.1) and R language (version 4.2.0) were used for subgroup analysis and interaction testing. P  = 0.05 was used as the statistical criterion.

The continuous variables are displayed as the mean ± standard deviation or as medians and quartiles (Q1-Q3), and group comparisons were conducted using the independent-samples t test or Mann‒Whitney U test according to the type of data distribution. Chi-square tests were used to compare differences among categorical variables, which are presented as frequencies or percentages. The data were analyzed for a normal distribution by the D’Agostino–Pearson omnibus normality test. The Kruskal‒Wallis test was used to assess the association between sASGR1 levels and the severity of CAD. A multivariate logistic regression model was used to identify the factors that influence the presence of CAD. The diagnostic value of sASGR1 and traditional biomarkers in patients with CAD was assessed using receiver operating characteristic (ROC) curves. To further analyze the relationship between sASGR1 and inflammatory markers, we employed a stepwise multivariate regression model in which inflammatory markers were used as the dependent variables. For subgroup analysis, stratified linear regression models were employed, and likelihood ratio tests were applied to find any variations or interactions.

Baseline characteristics

The basic details and biochemical characteristics of the study subjects are listed in Table  1 . BMI, smoking status, statin use, history of hypertension, and T2DM status were greater in the CAD group than in the non-CAD group ( P  < 0.05). The CAD group had higher serum TG, LDL-C, Lp(a), APO-B, and hs-CRP levels; WBC and neutrophil counts; and monocyte counts than did the non-CAD group ( P  < 0.05). HDL-C levels were greater in non-CAD patients ( P  < 0.05). There were no significant differences in age, sex, lymphocyte count, or other blood lipid parameters between the two patient groups.

Serum sASGR1 levels in the CAD and non-CAD groups

As shown in Fig.  1 , the serum level of sASGR1 in CAD patients was significantly greater than that in non-CAD patients [2.58 (1.8, 4.1) vs. 1.71 (1.3, 2.6) ng/ml, P  < 0.0001]. Subsequently, we investigated the relationship between sASGR1 levels and the severity of CAD. As shown in Fig.  2 A, a lack of significant difference was observed between CAD patients with ≤ 2 diseased vessels and non-CAD patients [2.12 (1.5, 3.0) vs. 1.71 (1.3, 2.6) ng/ml, P  = 0.078]. However, the level of sASGR1 in CAD patients with > 2 diseased vessels was significantly greater than that in non-CAD patients [2.76 (2.2, 4.8) vs. 1.71 (1.3, 2.6) ng/ml, P  < 0.0001] or in CAD patients with ≤ 2 diseased vessels [2.76 (2.2, 4.8) vs. 2.12 (1.5, 3.0) ng/ml, P  = 0.033]. Additionally, we separated patients into two groups according to the median (60) Gensini score to assess the association between sASGR1 level and CAD severity more precisely: Gensini score ≤ 60 ( n  = 45) and Gensini score > 60 ( n  = 45). However, there was no significant increase in the level of sASGR1 as the Gensini score increased (Fig.  2 B). In addition, we were unable to identify significant differences in the severity of CAD between individuals with and without AMI (Fig.  2 C).

Comparison of serum sASGR1 levels between the CAD and non-CAD groups. The serum sASGR1 concentration in CAD patients ( n  = 90) was significantly greater than that in non-CAD patients ( n  = 70). [Mann‒Whitney U test, 2.58 (1.8, 4.1) vs. 1.71 (1.3, 2.6) ng/ml, P  < 0.0001]. **** P  < 0.0001

The relationship between sASGR1 levels and the severity of CAD. ( A ) sASGR1 levels in patients with different CAD statuses and numbers of involved vessels. Comparisons were evaluated by the Kruskal‒Wallis test. ns, not statistically significant. * P  < 0.05. **** P  < 0.0001. For vessels ≤ 2, the number of involved vessels was < 2; for vessels > 2, the number of involved vessels was more than 2. ( B ) Comparison of sASGR1 levels in patients with different Gensini scores. Comparisons were evaluated by the Kruskal‒Wallis test. ns, not statistically significant. * P  < 0.05. ** P  < 0.01. ( C ) sASGR1 levels in patients with different severities of CAD. Comparisons were evaluated by the Kruskal‒Wallis test. ns, not statistically significant. * P  < 0.05. *** P  < 0.001

Diagnostic value of sASGR1 and traditional biomarkers for CAD patients

We used receiver operating characteristic (ROC) curves to evaluate the diagnostic ability of sASGR1 levels for CAD (Fig.  3 ). The area under the curve (AUC) of sASGR1 was 0.691 (95% CI = 0.60–0.78, P  < 0.001). Its diagnostic utility was better than that of the traditional biomarkers APO-B (AUC: 0.619, 95% CI: 0.53–0.71, P  = 0.023) and LDL-C (AUC: 0.599, 95% CI: 0.50–0.69, P  = 0.059), despite not being comparable to that of hs-CRP (AUC: 0.775, 95% CI: 0.70–0.85, P  < 0.001), TG (AUC: 0.796, 95% CI: 0.72–0.87, P  < 0.001), or total cholesterol (TC)/high-density lipoprotein cholesterol (HDL-C) (AUC: 0.723, 95% CI: 0.64–0.81, P  < 0.001). sASGR1 has a cutoff value of 1.682 ng/ml for predicting the occurrence of CAD, with a sensitivity of 77.6% and a specificity of 54.2%. The sensitivity and specificity of the other biomarkers for predicting the presence of CAD were as follows: hs-CRP (sensitivity: 47.1%, specificity: 95.8%), APO-B (sensitivity: 41.2%, specificity: 87.5%), LDL-C (sensitivity: 35.3%, specificity: 91.7%), TC/HDL-C (sensitivity: 69.4%, specificity: 70.8%), and TG (sensitivity: 62.4%, specificity: 89.6%).

ROC curve analysis for the predictive value of serum sASGR1 and traditional biomarkers in the presence of CAD

sASGR1 is an independent influencing factor for the occurrence of CAD

A multivariate logistic regression model was used to identify the factors that influence the presence of CAD. We included independent variables based on the results of univariate analysis, clinical significance, sample size, and multicollinearity. The results showed that sASGR1, smoking, TG, hypertension, and T2DM were associated with an increased risk of CAD after controlling for BMI, smoking status, TG, LDL-C, hs-CRP, hypertension, and T2DM (Table  2 ). For every unit increase in the sASGR1 level, the risk of CAD increased by 0.52 times (OR = 1.522, 95% CI = 1.095, 2.115; P  = 0.012).

Relationships between the serum sASGR1 concentration and inflammatory marker level

By setting hs-CRP levels, WBC counts, and WBC subsets as dependent variables, we used stepwise multivariate regression models to determine the correlation between sASGR1 levels and inflammatory marker levels (Table  3 ). After we adjusted for sex, age, BMI, smoking status, statin use, hypertension status, T2DM status, and CAD status (Model II), sASGR1 was positively associated with the levels of inflammatory markers [hs-CRP ( β  = 1.00, p  < 0.001), WBC count ( β  = 0.12, P  = 0.004), and neutrophil count ( β  = 0.09, P  = 0.011)]. Given that previous research has indicated a link between blood lipid levels and inflammation [ 39 ], we further adjusted for blood lipid parameters and found that the serum sASGR1 concentration was significantly positively correlated with the serum hs-CRP level ( β  = 0.86, P  < 0.001), WBC count ( β  = 0.13, P  = 0.004), and neutrophil count ( β  = 0.10, P  = 0.008). Additionally, a similar association was observed between sASGR1 concentration and monocyte count ( β  = 0.009, P  = 0.014).

Subgroup analysis of the correlation between sASGR1 and inflammatory marker levels

According to the interaction test (Table  4 ), the effect of sASGR1 on the hs-CRP level was significantly affected by age ( p for interaction = 0.015), sex ( p for interaction = 0.007), BMI ( p for interaction = 0.002), and hypertension status ( P for interaction = 0.019), indicating that the association between the sASGR1 concentration and the hs-CRP level differed according to these variables. Notably, even after we adjusted for factors such as age, sex, BMI, statin use, smoking status, and lipid parameters, the positive correlation between sASGR1 and hs-CRP levels was still significant in patients with CAD ( β  = 0.8, P  < 0.001). Among patients without CAD, this correlation was not observed ( P  = 0.231).

Similarly, we also conducted subgroup analysis and interaction testing to determine the relationship between sASGR1 and WBC count. Age was the sole significant factor influencing the association between sASGR1 level and WBC count, in contrast to hs-CRP ( P for interaction < 0.001), as shown in Table  5 . Interestingly, similar to that of hs-CRP, a positive correlation between sASGR1 and WBC was observed only in CAD patients ( β  = 0.1, P  = 0.029).

According to our study, sASGR1 is independently and positively correlated with hs-CRP and WBC. According to our subgroup analysis, this relationship existed only for CAD patients. In addition, serum sASGR1 levels are elevated in CAD patients. sASGR1 is independently correlated with the risk of CAD after adjusting for confounding variables, and it has better diagnostic value than APO-B and LDL-C.

Since 2016, ASGR1 has received widespread attention from researchers due to its involvement in liver cholesterol metabolism [ 22 ]. Recent animal studies have shown that inhibiting ASGR1 on the hepatocyte membrane (named hASGR1) is expected to become a new strategy for reducing LDL-C levels [ 21 ]. Similarly, genetically mimicked ASGR1 inhibitors were associated with lower cholesterol levels and CAD risk [ 40 ]. In addition, an observational study showed that ASGR1 mRNA levels in peripheral blood mononuclear cells were lower in CAD patients than in non-CAD patients, but the underlying mechanism is still unknown [ 23 ]. However, there is currently no research on the role of serum sASGR1 in CAD patients. sASGR1 and LDL-C levels were found to be positively correlated in our recent study [ 31 ]. As expected, this study showed an increase in sASGR1 levels in CAD patients, which is consistent with the findings of a recent study [ 41 ]. In the present study, plasma proteomics analysis revealed ASGR1 to be a risk factor for ischemic heart disease. Thus, the results of our study lend support for sASGR1 as a potential biomarker for CAD. We also found that, after controlling for confounding variables, sASGR1 remained an independent risk factor for CAD (Table  2 ). As mentioned earlier, hASGR1 regulates liver cholesterol homeostasis by binding to circulating asialoglycoproteins, ultimately affecting plasma cholesterol levels and the risk of CAD [ 21 , 22 ]. Previous research revealed that while sASGR1 inhibits the binding of circulating asialoglycoproteins to hASGR1, it still binds to asialoglycoproteins and enters the liver as a complex [ 30 , 31 ]. Taken together, these findings imply that the entry of the sASGR1-asialoglycoprotein complex into hepatocytes may exert similar downstream biological effects as the binding of the asialoglycoprotein to hASGR1. Another hypothesis, however, is that the serum sASGR1 concentration might reflect the hASGR1 protein level. Given this, it will be intriguing to investigate whether blocking sASGR1 can lower plasma cholesterol and the risk of CAD in a manner similar to inhibiting hASGR1.

We evaluated the relationship between serum sASGR1 levels and the severity of CAD. Although the serum sASGR1 concentration was associated with the number of coronary artery lesions (Fig.  2 A), the level of sASGR1 did not significantly increase as the Gensini score increased (Fig.  2 B). The serum sASGR1 concentration has been reported to be positively correlated with LDL-C levels [ 31 ], but the correlation between LDL-C level and Gensini score is not significant [ 42 , 43 ]. The relationship between serum sASGR1 levels and the severity of CAD in this study remains uncertain, even though the Gensini score is a more accurate indicator of plaque burden and CAD severity than the number of vascular lesions. More precise methods, such as intravascular ultrasound and optical coherence tomography, may be needed to evaluate the relationship between sASGR1 and the severity of CAD. We failed to find that sASGR1 could be used to identify individuals who had an AMI (Fig.  2 C). Our previous study showed that there is no correlation between the serum troponin T concentration and sASGR1 level [ 31 ], which is consistent with the results of this study, indicating that the sASGR1 level is not related to the degree of myocardial injury.

We analyzed the diagnostic value of the sASGR1 level for CAD. Although it does not have the same diagnostic efficacy as hs-CRP, it is superior to LDL-C and APO-B. In addition, sASGR1 has advantages over hs-CRP (47.1%), APO-B (41.2%), TG (62.4%), and TC/HDL-C (69.4%) due to its relatively high diagnostic sensitivity (77.6%), indicating an advantage in the early screening of CAD.

In addition to its clear association with cholesterol metabolism, a small number of studies have shown that ASGR1 is associated with systemic inflammation. The most direct evidence shows that knockdown of Asgr1 in mouse liver and monocytes suppressed the expression of plasma inflammatory cytokines [interleukin-1 (IL-1), IL-6, and tumor necrosis factor (TNF-α)] [ 27 ]. However, these studies on the relationship between ASGR1 and systemic inflammation have focused mainly on the role of ASGR1 as a hepatocyte or monocyte membrane receptor. The relationships between serum sASGR1 levels and inflammatory marker levels in healthy individuals and patients with disease are unknown. Our findings showed that the serum sASGR1 concentration is positively correlated with inflammatory marker levels (hs-CRP and WBC), which supports and propels previous basic research. However, the causal link between sASGR1 and inflammatory markers warrants further exploration.

Inflammation is a key factor in the development of atherosclerosis and CAD. As a stable and reliable inflammatory marker, CRP has been shown to upregulate the expression of adhesion molecules and monocyte chemokines, inhibit the production of endothelial nitric oxide synthase (eNOS), and promote arterial thrombosis, indicating direct involvement in the occurrence of atherosclerosis [ 44 , 45 , 46 ]. Therefore, evaluating hs-CRP levels is highly important for CAD patients without hypercholesterolemia, as there is no urgent demand for lipid-lowering agents. The CANTOS study identified for the first time the ability of anti-inflammatory treatment to reduce cardiovascular events, which was independent of blood lipid levels [ 47 ]. An association between plasma CRP and LDL-C levels has been demonstrated in previous research [ 39 ]. Despite the fact that ASGR1 does affect circulating cholesterol levels, our subgroup analysis results showed that sASGR1 remains an independent influencing factor for hs-CRP and WBC count among individuals with CAD even after adjusting for lipid parameters (Table  3 ). Notably, patients without CAD did not exhibit this association (Tables  4 and 5 ). Thus, our findings suggest a potential connection between serum sASGR1 and inflammation in patients with CAD, independent of lipid metabolism disorders. This hypothesis has actually received indirect support from earlier studies. For instance, sialylation mediated by α2,3-sialyltransferases has been linked to the recruitment of circulating inflammatory myeloid cells to the atherosclerotic vascular endothelium [ 22 , 48 , 49 ]. Moreover, sASGR1 levels and monocyte counts were positively correlated according to the multivariate regression model (model III: β  = 0.009, p  = 0.014). ASGR1 is expressed in peripheral blood monocytes [ 50 ]. These findings suggest that, in addition to being secreted by hepatocytes, serum sASGR1 may also be secreted by monocytes. In summary, the positive correlation between the serum sASGR1 concentration and inflammatory marker (hs-CRP and WBC) levels in CAD patients supports the current view that ASGR1 is a risk factor for CAD. In addition, our research provides a reference for revealing the potential role of sASGR1 in the inflammation of atherosclerosis.

Study strengths and limitations

This is the first study in which we investigated the relationship between serum sASGR1 levels and CAD incidence, as well as inflammatory marker levels. This study has several limitations. First, this was a cross-sectional investigation, and the causal relationships between the serum sASGR1 concentration and CAD incidence or inflammatory marker levels could not be determined. However, further studies are needed to reveal the role of ASGR1 in the inflammation of atherosclerosis. Second, a relatively small sample size may hinder the ability to identify minute differences, even though the results of sample size calculations show that our sample size is appropriate for the main purpose of the study. These findings need to be confirmed in larger-sample studies. Third, the method of dividing the patients into groups with and without CAD may have resulted in selection bias. Fourth, we did not perform Western blot analysis of the serum sASGR1 concentration to confirm that this parameter is a biomarker for CAD, as suitable antibodies were not found. Finally, we did not investigate the correlation between sASGR1 levels and the levels of other inflammatory cytokines, such as ILs.

Conclusions

Our study suggested that serum sASGR1 levels are elevated in CAD patients and may be an independent risk factor for CAD. Moreover, sASGR1 was independently and positively correlated with inflammatory marker levels in CAD patients, even after controlling for lipid parameters. The potential role of sASGR1 in inflammation in atherosclerosis, independent of cholesterol metabolism, may need further study.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

Atherosclerotic cardiovascular disease

Asialoglycoprotein receptor 1

• Coronary artery disease

Soluble ASGR1

Hepatic ASGR1

High-sensitivity CRP

• White blood cell count

Low-density lipoprotein cholesterol

High-density lipoprotein cholesterol

Vascular cell adhesion molecule-1

Intercellular adhesion molecule-1

Monocyte chemotactic protein-1

Apolipoprotein B

Apolipoprotein A1

Triglyceride

Total cholesterol

Lipoprotein (a)

Interleukin-1

Tumor necrosis factor

Epidermal growth factor receptor

Acute myocardial infarction

Type 2 Diabetes Mellitus

Body mass index

Receiver operating characteristic

Area under the curve

Enzyme-linked immunosorbent assay

Confidence interval

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Acknowledgements

We would like to express our gratitude to all those who helped us during the writing of this manuscript.

This work was supported by the National Natural Science Foundation of China [grant number 82100495 to F. Luo, grant number 82201879 to J.F. Chen]; the Hunan Provincial Natural Science Foundation of China [grant number 2021JJ40852 to F. Luo, grant number 2022JJ40675 to J.F. Chen]; the Scientific Research Project of Hunan Provincial Health Commission [grant number 202203014009 to F. Luo, grant number B202305037231 to J.F. Chen]; the Scientific Research Launch Project for New Employees of the Second Xiangya Hospital of Central South University [to F. Luo and J.F. Chen]; the China Postdoctoral Science Foundation [grant number 331046 and 2023T160738 to F. Luo and J.F. Chen]; and the Key Research and Development Program of Hunan Province of China [grant number 2021SK2004 to Z.F. Fang].

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Qin Luo, Yanfeng Yi, Panyun Wu, Zhangling Chen, Jianjun Tang, Zhenfei Fang & Fei Luo

Research Institute of Blood Lipids and Atherosclerosis, the Second Xiangya Hospital, Central South University, Changsha, China

Reproductive Medicine Center, Department of Obstetrics and Gynecology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China

Jingfei Chen

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FL, ZF and QL conceived the idea. QL wrote the manuscript; JC, YY and PW conducted the data collection and analysis. FL, ZC, YS, HAA, JT and ZF read through and corrected the manuscript. All authors read and approved the final manuscript.

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Luo, Q., Chen, J., Yi, Y. et al. The serum soluble ASGR1 concentration is elevated in patients with coronary artery disease and is associated with inflammatory markers. Lipids Health Dis 23 , 89 (2024). https://doi.org/10.1186/s12944-024-02054-8

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Lipids with potential health benefits in herbal teas identified

by Hokkaido University

Herbal teas are enjoyed worldwide, not only for their taste and refreshment but also for a wide range of reputed health benefits. But the potential significance of a category of compounds called lipids in the teas has been relatively unexplored.

Researchers at Hokkaido University, led by Associate Professor Siddabasave Gowda and Professor Shu-Ping Hui of the Faculty of Health Sciences, have now identified 341 different molecular species from five categories of lipids in samples of four types of herbal tea. They published their results in the journal Food Chemistry .

Lipids are a diverse collection of natural substances that share the property of being insoluble in water. They include all of the fats and oils that are common constituents of many foods, but they have generally not been examined as significant components of teas.

The Hokkaido team selected four teas for their initial analysis : dokudami (Houttuynia cordata, fish mint), kumazasa (Sasa veitchii), sugina (Equisetum arvense, common horsetail) and yomogi (Artemisia princeps, Japanese mugwort).

"These herbs are native to Japan and have been widely consumed as tea from ancient times due to their medicinal properties," says Gowda. The medicinal benefits attributed to these and other herbal teas include antioxidant, antiglycation, anti-inflammatory, antibacterial, antiviral, anti-allergic, anticarcinogenic, antithrombotic, vasodilatory, antimutagenic, and anti-aging effects.

The lipids in the teas were separated and identified by combining two modern analytical techniques called high-performance liquid chromatography and linear ion trap-Orbitrap mass spectrometry.

The analysis revealed significant variations in the lipids in the four types of tea, with each type containing some known bioactive lipids. These included a distinct category of lipids called short-chain fatty acid esters of hydroxy fatty acids (SFAHFAs), some of which had never previously been found in plants. SFAHFAs detected in tea could be a novel source of short-chain fatty acids, which are essential metabolites for maintaining gut health.

"The discovery of these novel SFAHFAs opens new avenues for research," says Hui, adding that the lipid concentrations found in the teas are at levels that could be expected to have significant nutritional and medical effects in consumers.

The lipids discovered also included α-linolenic acid, already known for its anti-inflammatory properties, and arachidonic acid which has been associated with a variety of health benefits . These two compounds are examples of a range of poly-unsaturated fatty acids found in the teas, a category of lipids that are well-known for their nutritional benefits.

"Our initial study paves the way for further exploration of the role of lipids in herbal teas and their broad implications for human health and nutrition," Gowda concludes. "We now want to expand our research to characterize the lipids in more than 40 types of herbal tea in the near future."

Journal information: Food Chemistry

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The emerging role of lipidomics in prediction of diseases

• Xianlin Han   ORCID: orcid.org/0000-0002-8615-2413 1 , 2  

Nature Reviews Endocrinology volume  18 ,  pages 335–336 ( 2022 ) Cite this article

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A recent paper published in PLoS Biology reported the application of lipidomics in predicting the incidence of type 2 diabetes mellitus and cardiovascular diseases in a population cohort. The study demonstrates the role of lipidomics in prediction of diseases and translational research, which could herald the beginning of an era of quantitative lipidomics.

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Han, X. & Gross, R. W. The foundations and development of lipidomics. J. Lipid Res. 63 , 100164 (2022).

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Acknowledgements

The author acknowledges the support of by National Institutes of Health P30 AG013319, P30 AG044271, P30 AG066546 (Biomarker Core), U19 AG069701, and U54 NS110435.

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Diazobutanone-assisted isobaric labelling of phospholipids and sulfated glycolipids enables multiplexed quantitative lipidomics using tandem mass spectrometry.

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Prioritize biologically relevant ions for data-independent acquisition (BRI-DIA) in LC–MS/MS-based lipidomics analysis

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Scalable synthesis of lipid nanoparticles for nucleic acid drug delivery using an isometric channel-size enlarging strategy

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• Zesen Ma 1 , 2   na1 ,
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Lipid nanoparticles (LNPs) have emerged as highly effective delivery systems for nucleic acid-based therapeutics. However, the broad clinical translation of LNP-based drugs is hampered by the lack of robust and scalable synthesis techniques that can consistently produce formulations from early development to clinical application. In this work, we proposed a method to achieve scalable synthesis of LNPs by scaling inertial microfluidic mixers isometrically in three dimensions. Moreover, a theoretical predictive method, which controls the mixing time to be equal across different chips, is developed to ensure consistent particle size and size distribution of the synthesized LNPs. LNPs loaded with small interfering RNA (siRNA) were synthesized at different flow rates, exhibiting consistent physical properties, including particle size, size distribution and encapsulation efficiency. This work provides a practical approach for scalable synthesis of LNPs consistently, offering the potential to accelerate the transition of nucleic acid drug development into clinical application.

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Acknowledgements

This research work has been supported in part by Collaborative Innovation Program of Hefei Science Center, CAS (No. 2022HSC-CIP001), Anhui Province Key Laboratory of High Field Magnetic Resonance Imaging (No. KFKT-2022-0003), Joint Research Fund for Overseas Chinese, Hong Kong and Macao Young Scholars (No. 51929501), National Key R&D Program of China (No. 2022YFF0705002). The authors would like to acknowledge the USTC Experimental Center of Engineering and Material Sciences and the USTC center for Micro-and Nanoscale Research and Fabrication for technical support in microfabrication. The authors would like to acknowledge Wulin Zhu for the assistance in fabrication of microfluidic chip.

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Zesen Ma and Haiyang Tong contributed equally to this work.

Authors and Affiliations

Department of Precision Machinery and Precision Instrumentation, University of Science and Technology of China, Hefei, 230027, China

Zesen Ma, Sijin Lin, Baoqing Li & Jiaru Chu

Key Laboratory of Precision Scientific Instrumentation of Anhui Higher Education Institutes, University of Science and Technology of China, Hefei, 230027, China

Science Island Branch, Graduate School, University of Science and Technology of China, Hefei, 230026, China

Haiyang Tong

Anhui Provincial Key Laboratory of High Field Magnetic Resonance Imaging, High Magnetic Field Laboratory, Hefei Institute of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China

Haiyang Tong & Changlin Tian

Anhui Provincial Engineering Laboratory of Peptide Drugs, University of Science and Technology of China, Hefei, 230027, China

Li Zhou, Demeng Sun & Changlin Tian

School of Biomedical Engineering, Division of Life Sciences and Medicine, University of Science and Technology of China, Suzhou, 215127, China

Baoqing Li & Changlin Tian

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Correspondence to Baoqing Li or Changlin Tian .

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Ma, Z., Tong, H., Lin, S. et al. Scalable synthesis of lipid nanoparticles for nucleic acid drug delivery using an isometric channel-size enlarging strategy. Nano Res. 17 , 2899–2907 (2024). https://doi.org/10.1007/s12274-023-6031-1

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Received : 21 June 2023

Revised : 20 July 2023

Accepted : 22 July 2023

Published : 14 August 2023

Issue Date : April 2024

DOI : https://doi.org/10.1007/s12274-023-6031-1

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