Phospholipids In Idl
Introduction
Section titled “Introduction”Phospholipids are fundamental components of biological membranes and play crucial roles in lipid transport and metabolism within the human body. Intermediate-density lipoprotein (IDL) is a type of lipoprotein particle that represents a transitional stage in the metabolic pathway from very low-density lipoproteins (VLDL) to low-density lipoproteins (LDL).[1] Phospholipids are integral to the structure and function of IDL, contributing to its stability and interactions with enzymes and receptors. Understanding the intricate relationship between phospholipids and IDL is vital for comprehending lipid homeostasis and its implications for human health.
Biological Basis
Section titled “Biological Basis”The structure of phospholipids in IDL is complex and can vary in their fatty acid side chains. For instance, the glycerol moiety can contain ester (a) or ether (e) bonds, leading to classifications such as diacyl (aa), acyl-alkyl (ae), or dialkyl (ee) phospholipids. The lipid side chain composition is abbreviated by the number of carbons (x) and double bonds (y), such as “PC ae C33:1” for a plasmalogen/plasmenogen phosphatidylcholine with specific carbon and double bond counts.[1]
Genetic factors significantly influence phospholipid composition and overall lipid metabolism. Genome-wide association studies (GWAS) have identified numerous genetic loci associated with circulating lipid levels, including those that impact phospholipids within lipoproteins like IDL. For example, variants in the FADS1 gene cluster are strongly associated with the fatty acid composition in phospholipids, particularly long-chain poly-unsaturated fatty acids. [1] Strong associations have been observed between FADS1genotypes and glycerophospholipid species such as phosphatidylcholines (PC), phosphatidylethanolamines (PE), and phosphatidylinositols (PI), including plasmalogen/plasmenogen phospholipids.[1] These associations suggest a modification in the efficiency of fatty acid delta-5 desaturase reaction, which can lead to altered levels of various phospholipid species. [1]
Other genes implicated in lipid metabolism, which would affect phospholipid composition and IDL levels, include ABCA1, APOB, CELSR2, CETP, DOCK7, GALNT2, GCKR, HMGCR, LDLR, LIPC, LIPG, LPL, MLXIPL, NCAN, PCSK9, and TRIB1, as well as gene clusters like MVK-MMAB, APOA5-APOA4-APOC3-APOA1, and APOE-APOC1-APOC4-APOC2. [2] For instance, a polymorphism rs4775041 has been linked to phosphatidylethanolamines and has weak associations with type 2 diabetes and blood cholesterol levels. [1] Furthermore, LIPC promoter variants are associated with lower hepatic lipase activity and higher HDL cholesterol [3]which indicates its role in lipoprotein remodeling that would impact IDL.
Clinical Relevance
Section titled “Clinical Relevance”Abnormal serum lipid levels are well-established determinants of cardiovascular disease (CVD).[2]The phospholipids within IDL, being part of the lipoprotein cascade, are intrinsically linked to the overall lipid profile and, consequently, to CVD risk. Genetic variations affecting phospholipid composition and IDL metabolism can contribute to dyslipidemia, a major risk factor for heart disease.[3] While common genetic variants have been identified, they explain only a fraction of the variation in lipid concentrations within the population, highlighting the polygenic nature of dyslipidemia. [2]Understanding the specific roles of phospholipids in IDL and how genetic variations influence their levels can provide insights into disease mechanisms and potential therapeutic targets.
Social Importance
Section titled “Social Importance”Cardiovascular diseases remain a leading cause of morbidity and mortality worldwide. Research into the genetic and metabolic underpinnings of lipid profiles, including phospholipids in IDL, is crucial for improving public health. Identifying genetic variants that influence phospholipid composition and IDL levels can help in personalizing risk assessment for CVD. Furthermore, these metabolic traits can serve as intermediate phenotypes, bridging the gap between genetic variations and complex diseases, paving the way for more targeted prevention and treatment strategies.[1] The continuous discovery of new loci and genes involved in lipid metabolism underscores the complexity of these pathways and their significant impact on population health.
Limitations
Section titled “Limitations”Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”The research employed stringent statistical thresholds (P < 5 × 10-8) for genome-wide significance, which is crucial for minimizing false positives. However, this rigorous approach also means that some true genetic associations with effects on intermediate-density lipoprotein or related lipid traits, particularly those with smaller effect sizes, might not have met the prespecified significance criteria.[3] For example, while the LPA coding SNP rs3798220 showed a strong association with lipoprotein(a) levels, its association with LDL cholesterol reached a P-value of 3 × 10-7, falling short of the primary threshold.[3] Such instances suggest potential for false negatives and highlight areas where larger cohorts or meta-analyses might be needed to definitively confirm weaker signals, thereby impacting a complete understanding of the genetic architecture influencing phospholipid metabolism in lipoproteins.
Phenotypic Resolution and Measurement Scope
Section titled “Phenotypic Resolution and Measurement Scope”While the study meticulously assessed various lipoprotein particle concentrations, including intermediate-density lipoproteins, and several apolipoproteins likeAPOA-I and APOC-III, its focus was primarily on the overall concentrations and levels of these entities. [3]The provided context does not detail the specific molecular composition of these lipoproteins, particularly the phospholipid content of intermediate-density lipoproteins. Consequently, while insights into the genetic determinants of lipoprotein particle numbers are provided, the direct genetic influences on thephospholipid proportion or specific phospholipid species within IDL particles remain underexplored. This limitation restricts a comprehensive understanding of how genetic variants specifically modulate phospholipid metabolism and distribution within intermediate-density lipoproteins, offering a high-level view rather than a granular molecular breakdown.
Generalizability and Unaccounted Factors
Section titled “Generalizability and Unaccounted Factors”A significant limitation pertains to the generalizability of the findings, as the ancestry of the study cohorts is not specified in the provided context, potentially biasing results towards populations of European descent if such cohorts were predominantly used. Furthermore, the study does not explicitly account for environmental factors such as diet, lifestyle, or other external influences that are known to profoundly impact lipid metabolism and could modify genetic effects. The observed genetic associations represent only a portion of the heritable variation in lipid traits, indicating that a substantial fraction of “missing heritability” likely remains to be discovered, possibly due to the influence of rare variants, complex gene-gene interactions, or unmeasured gene-environment interactions. Addressing these unmeasured confounders and exploring diverse populations would be crucial for a more complete understanding of the polygenic basis of lipid traits and phospholipids within intermediate-density lipoproteins.
Variants
Section titled “Variants”PCSK9(Proprotein Convertase Subtilisin/Kexin type 9) plays a pivotal role in regulating cholesterol levels by controlling the degradation of the low-density lipoprotein receptor (LDLR). Variants like rs11591147 , rs11206517 , and rs472495 can influence the activity of _PCSK9_, altering the number of LDLR proteins on the liver cell surface. Increased _PCSK9_activity leads to fewer _LDLR_s, higher levels of low-density lipoprotein (LDL) cholesterol, and can affect the clearance of intermediate-density lipoprotein (IDL) and its phospholipid content, asLDLR also binds IDL particles. Genetic variations in _PCSK9_, even those with lower frequencies, can have a notable impact on circulating LDL cholesterol concentrations. [3] These variations highlight _PCSK9_ as a key target in understanding and treating hypercholesterolemia, impacting pathways relevant to IDL particle metabolism and their phospholipid composition. [3]
The intergenic region near _SMARCA4_ and _LDLR_ includes variants such as rs73015024 and rs12151108 , which are implicated in regulating _LDLR_ expression. The LDLR is crucial for removing cholesterol-rich lipoproteins, including LDL and IDL, from the bloodstream; impaired LDLRfunction can lead to IDL accumulation and alter its phospholipid content, contributing to cardiovascular disease risk. Similarly, variants near_HMGCR_, like rs12916 , are significant because _HMGCR_(3-hydroxy-3-methylglutaryl-CoA reductase) is the rate-limiting enzyme in cholesterol synthesis. Genetic changes in this pathway can modify the overall cholesterol available for lipoprotein assembly and influence the liver’s clearance of IDL particles.[3] _CERT1_ (CERamide Transfer Protein 1), also associated with rs12916 , influences lipid transfer within cells, potentially affecting cellular lipid composition and indirectly impacting lipoprotein metabolism.[3]
Variants within the _APOB_ - _TDRD15_ region, specifically rs548145 and rs562338 , are highly relevant to IDL metabolism. _APOB_(Apolipoprotein B) is the primary structural protein of both LDL and IDL particles, essential for their formation and acting as the ligand forLDLR binding. Variations affecting _APOB_ can alter the structure or function of these lipoproteins, impairing their receptor recognition and clearance, which consequently influences IDL half-life and phospholipid composition. _TDRD15_ (Tudor Domain Containing 15) is thought to be involved in regulatory pathways that may indirectly affect lipid metabolism. [3] Genetic influences on _APOB_directly affect the liver’s capacity to produce and process very-low-density lipoprotein (VLDL), IDL, and LDL particles.[3]
Other genes like _ALDH1A2_, _LIPC_, _BCAM_, _CELSR2_, _PSRC1_, and _TOMM40_ also play diverse roles in regulating lipid profiles. _ALDH1A2_ (Aldehyde Dehydrogenase 1 Family Member A2) variants rs261290 and rs261291 , along with rs633695 (also near _LIPC_), may affect aldehyde metabolism, which can indirectly impact cellular lipid handling and potentially lipid peroxidation. _LIPC_ (Lipase C, Hepatic Type) is crucial for hydrolyzing triglycerides and phospholipids in various lipoproteins, including IDL, thereby facilitating their conversion to LDL and subsequent liver uptake. Variants like rs633695 can alter _LIPC_ activity, impacting the remodeling and phospholipid content of IDL particles. [3] The _CELSR2_ - _PSRC1_ intergenic region, encompassing variants like rs646776 and _CELSR2_ variant rs12740374 , is a well-established locus influencing cholesterol levels and potentially IDL metabolism through mechanisms still under investigation. _BCAM_ (Basal Cell Adhesion Molecule) variant rs118147862 and _TOMM40_ (Translocase Of Outer Mitochondrial Membrane 40) variant rs1160983 are also associated with lipid traits; _TOMM40_ has connections to _APOE_and mitochondrial function, potentially influencing lipid processing and energy metabolism in ways that affect lipoprotein composition.[3]
Key Variants
Section titled “Key Variants”Biological Background
Section titled “Biological Background”Orchestration of Lipoprotein and Triglyceride Metabolism
Section titled “Orchestration of Lipoprotein and Triglyceride Metabolism”The human body meticulously manages the transport and storage of lipids, a process critical for energy supply and cellular function. At the heart of this system are lipoproteins, complex particles that carry fats, including triglycerides and cholesterol, through the bloodstream. The entire life cycle of these lipoproteins, encompassing their formation, activity, and eventual turnover, is tightly regulated by a diverse set of genetic factors. [4] Key to this regulation are apolipoproteins, structural proteins embedded within lipoproteins that facilitate their assembly, interact with enzymes, and serve as ligands for cellular receptors. For instance, genes such as APOE, APOB, and APOA5 encode specific apolipoproteins that are fundamental to these processes, directly influencing the circulating concentrations of various lipids. [4] Disruptions in the delicate balance of apolipoprotein function can therefore have far-reaching consequences for systemic lipid homeostasis.
Regulation of Lipid Synthesis and Cellular Handling
Section titled “Regulation of Lipid Synthesis and Cellular Handling”The intricate balance of lipid concentrations also depends on the precise control of their synthesis and cellular uptake pathways. Several genes contribute to these processes by encoding enzymes and transporters crucial for building and moving lipid molecules. For example, MLXIPL is a transcription factor that plays a role in activating the synthesis of triglycerides, thereby directly influencing the body’s fat storage capacity. [4] Similarly, MVK encodes an enzyme essential for cholesterol biosynthesis, the multi-step pathway that produces cholesterol within cells. [4] Beyond synthesis, cholesterol movement is managed by transporters such as ABCA1, which facilitates cholesterol efflux from cells, and CETP, which mediates the transfer of cholesterol esters between different lipoproteins. [4] Cellular uptake of lipoproteins is mediated by specific receptors, notably LDLR, which binds and internalizes cholesterol-rich particles, and SORT1, a potential endocytic receptor for LPL, influencing how lipoproteins are cleared from circulation. [4]
Enzymatic Modulation of Lipid Breakdown and Receptor Interactions
Section titled “Enzymatic Modulation of Lipid Breakdown and Receptor Interactions”Efficient removal and degradation of lipids are as important as their synthesis and transport for maintaining healthy lipid levels. A family of enzymes known as lipases, including LPL, LIPC, and LIPG, plays a central role in hydrolyzing triglycerides within lipoproteins, releasing fatty acids for energy or storage. [4] The activity of these lipases can be fine-tuned by inhibitory proteins, such as ANGPTL3, which acts to reduce lipase function and thus can increase circulating triglyceride levels.[4] Furthermore, the body also manages cholesterol degradation, a process involving proteins like MMAB, which contributes to the breakdown of cholesterol. [4]Receptor function, critical for lipoprotein binding and cellular uptake, can also be modulated by glycosyltransferases likeB4GALT4, B3GALT4, and GALNT2, which are involved in attaching sugar molecules to proteins and potentially altering the properties of lipoprotein receptors.[4]
Genetic Contributions to Systemic Lipid Homeostasis
Section titled “Genetic Contributions to Systemic Lipid Homeostasis”The interplay of these molecular and cellular mechanisms collectively dictates an individual’s lipid concentrations, which in turn significantly influences the risk of conditions like coronary artery disease. Studies have identified numerous genetic loci with variants that impact the entire cycle of lipoprotein and triglyceride metabolism.[4] While many identified genes have clear roles as apolipoproteins, enzymes, transporters, or receptors, other loci, such as those near TRIB1 and within the region surrounding NCAN, currently lack obvious functional candidates. [4] These unidentified genetic contributions highlight the complex and polygenic nature of lipid regulation and suggest that a substantial portion of the variation in lipid concentrations in the population remains to be explained by further research. [4]
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Metabolic Pathways and Phospholipid Biosynthesis
Section titled “Metabolic Pathways and Phospholipid Biosynthesis”The intricate synthesis and breakdown of phospholipids are central to maintaining cellular and systemic lipid homeostasis. The fatty acid desaturase enzyme, encoded by FADS1, plays a crucial role in converting essential fatty acids into long-chain poly-unsaturated fatty acids, such as the conversion of eicosatrienoyl-CoA (C20:3) to arachidonyl-CoA (C20:4). [1] This metabolic step directly influences the composition of various glycerophospholipids, including phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylinositol (PI), by determining the availability of specific fatty acyl chains for their synthesis. [1] Similarly, the MLXIPL gene coordinates the transcriptional regulation of enzymes that channel glycolytic end-products into lipogenesis and energy storage, thus controlling the de novo synthesis of lipid components that eventually form phospholipids. [5] These pathways are further interconnected with fundamental lipid metabolism, as exemplified by the mevalonate pathway, regulated by enzymes like HMGCR, which is vital for cholesterol synthesis and thereby influences the broader lipid environment in which phospholipids reside. [6]
Lipoprotein Remodeling and Phospholipid Catabolism
Section titled “Lipoprotein Remodeling and Phospholipid Catabolism”The dynamic remodeling of lipoproteins, including IDL, involves specific enzymes that modulate their phospholipid content. Lipoprotein lipase (LPL) hydrolyzes triglycerides within lipoproteins, a process that significantly alters lipoprotein particle size and composition, indirectly affecting the phospholipid-to-cholesterol ratio and phospholipid transfer.[2] Hepatic lipase C, encoded by LIPC, directly hydrolyzes phospholipids and triglycerides on lipoprotein surfaces, influencing their catabolism and the interconversion of different lipoprotein classes.[2] Genetic variations affecting the substrate specificity or activity of LIPC can therefore impact the efficiency of phospholipid metabolism within lipoproteins. [1] Apolipoproteins, such as apolipoprotein CIII (APOCIII), are integral to lipoprotein structure and function; increasedAPOCIII and reduced APOEon very low-density lipoprotein (VLDL) particles are associated with diminished VLDL fractional catabolic rates, leading to hypertriglyceridemia and affecting the overall phospholipid landscape of circulating lipoproteins.[7]
Genetic and Transcriptional Regulation of Lipid Homeostasis
Section titled “Genetic and Transcriptional Regulation of Lipid Homeostasis”Genetic variations play a significant role in regulating the pathways governing phospholipid levels and composition. A polymorphism in the FADS1 gene, for example, can reduce the efficiency of the delta-5 desaturase reaction, altering the balance between specific polyunsaturated fatty acids and consequently changing the concentrations of various glycerophospholipids. [1] The gene MLXIPL acts as a transcriptional regulator, coordinating the expression of enzymes involved in lipid synthesis, and its genetic variants, such as rs3812316 , have been directly linked to plasma triglyceride levels, highlighting its control over lipid flux and ultimately phospholipid precursor availability.[5] Beyond transcriptional control, post-translational regulatory mechanisms, such as alternative splicing of HMGCR exon13, can also impact enzyme function and downstream lipid pathways. [8] The identification of Tim4 as a phosphatidylserine receptor indicates a signaling pathway where specific phospholipids can mediate cellular recognition and regulatory responses. [9]
Interconnectedness and Systems-Level Integration
Section titled “Interconnectedness and Systems-Level Integration”The regulation of phospholipids involves a highly integrated network of pathways, where changes in one component can have broad systemic effects. Analyzing ratios of metabolite concentrations, such as [PC aa C36:4]/[PC aa C36:3], can provide a powerful indicator for the efficiency of specific enzymatic reactions like the FADS1 delta-5 desaturase, revealing interconnectedness at a systems level. [1] These metabolic traits serve as intermediate phenotypes, effectively linking genetic variations to complex diseases by reflecting the functional output of genetic differences. [1] The widespread impact of a single FADS1polymorphism on multiple glycerophospholipid species, including phosphatidylcholine, phosphatidylethanolamine, and plasmalogen/plasmenogen phospholipids, illustrates extensive pathway crosstalk and emergent properties within lipid metabolic networks.[1]
Dysregulation and Disease Implications
Section titled “Dysregulation and Disease Implications”Dysregulation within phospholipid pathways can contribute to various disease states, particularly those related to lipid disorders. Genetic polymorphisms associated with phospholipids, such as those inLIPC, have been weakly linked to complex conditions like type 2 diabetes, bipolar disorder, and rheumatoid arthritis.[1] These associations suggest that alterations in phospholipid metabolism may play a role in the pathogenesis of these diseases, extending their impact beyond direct lipid levels. [1]The genetic variants that influence phospholipid profiles and blood cholesterol levels hint at a potential causal relationship with disease, underscoring the importance of these pathways as therapeutic targets.[1]Moreover, the strong associations between certain genetic variants and the fatty acid composition in phospholipids indicate a predisposition to dyslipidemia and cardiovascular disease risk.[10]
Clinical Relevance
Section titled “Clinical Relevance”Role in Dyslipidemia and Cardiovascular Risk
Section titled “Role in Dyslipidemia and Cardiovascular Risk”Phospholipids, particularly those integrated within intermediate-density lipoproteins (IDL), are crucial components of lipid metabolism, and their dysregulation is intrinsically linked to cardiovascular disease (CVD) risk. Alterations in plasma phospholipid fatty acid concentrations, which are influenced by the de novo lipogenesis pathway, can serve as valuable biomarkers for metabolic perturbations, reflecting an individual’s susceptibility to dyslipidemia and its long-term cardiovascular implications.[11] Furthermore, specific genetic factors, such as those impacting phospholipid transfer protein (PLTP) activity, influence overall lipoprotein profiles, including high-density lipoprotein (HDL) levels, which subsequently affect IDL remodeling and the progression of coronary heart disease.[12]
The interactions between apolipoproteins, such as apolipoprotein E (APOE) and CIII (APOC3), are instrumental in regulating HDL metabolism and significantly contribute to coronary heart disease risk, with direct implications for IDL clearance and phospholipid exchange.[13] An enhanced understanding of these intricate lipid and apolipoprotein dynamics facilitates improved risk stratification, enabling the identification of high-risk individuals who could benefit from early therapeutic interventions. Dietary strategies, such as the incorporation of fish oils rich in omega-3 fatty acids, have demonstrated efficacy in reducing plasma lipids, lipoproteins, and apoproteins in patients with hypertriglyceridemia, highlighting a direct clinical application for managing dyslipidemia. [14]
Genetic Determinants and Personalized Medicine
Section titled “Genetic Determinants and Personalized Medicine”Genetic variants significantly influence plasma phospholipid composition and broader lipoprotein metabolism, thereby opening avenues for personalized medicine approaches. Genome-wide association studies (GWAS) have successfully identified numerous loci associated with concentrations of specific plasma phospholipid fatty acids, especially those participating in de novo lipogenesis, and have elucidated the polygenic nature of dyslipidemia.[11] For instance, specific genotypes of APOEhave been identified as key determinants of hepatic very-low-density lipoprotein (VLDL) apoB secretion and can lead to substantial alterations in plasma lipids, directly influencing IDL levels and associated phospholipids. [15]
These genetic insights are pivotal for precise risk stratification, allowing clinicians to identify individuals with an elevated predisposition to dyslipidemia or related complications and to tailor treatment selection accordingly. Understanding the genetic landscape, including variants in genes such as HSD17B13, TM6SF2, and PNPLA3, which regulate liver fat metabolism, triglyceride secretion, and hepatic lipid droplet content, can refine prognostic models for disease progression. This genetic information holds promise for informing highly targeted therapeutic strategies, moving towards a more personalized patient care model based on individual genetic profiles.[16]
Associations with Hepatic Disorders
Section titled “Associations with Hepatic Disorders”The metabolism of phospholipids in IDL and related lipid pathways is intricately linked to various hepatic disorders, predominantly nonalcoholic fatty liver disease (NAFLD). Aberrant lipid metabolism, including the activation ofPPARalphaby “new” hepatic fat and disruptions in calcium homeostasis leading to liver endoplasmic reticulum stress in obesity, are fundamental pathological mechanisms contributing to NAFLD.[17] The presence of the APOE4allele, for example, is associated with significant changes in plasma lipids and hyaluronic acid content in patients diagnosed with NAFLD, thereby influencing the disease’s clinical course and severity.[18]
Genetic factors that predispose to hepatic fat accumulation, such as variants in TM6SF2 and PNPLA3, directly impact the liver’s capacity to handle phospholipids by regulating triglyceride secretion and the content of hepatic lipid droplets.[19]This profound connection provides diagnostic utility, where specific lipid profiles, including phospholipid components, may serve as predictive indicators for NAFLD risk and severity. Moreover, these associations help to clarify the overlapping phenotypes between dyslipidemia and progressive liver disease, enabling comprehensive patient management.[20]
References
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[11] Wu JH, et al. “Genome-wide association study identifies novel loci associated with concentrations of four plasma phospholipid fatty acids in the de novo lipogenesis pathway: results from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.” Circulation: Cardiovascular Genetics, vol. 6, no. 1, 2013, pp. 118-125.
[12] Jiang XC, et al. “Targeted mutation of plasma phospholipid transfer protein gene markedly reduces high-density lipoprotein levels.” The Journal of Clinical Investigation, vol. 103, no. 7, 1999, pp. 907-914.
[13] Ko C, et al. “Apolipoproteins E and CIII interact to regulate HDL metabolism and coronary heart disease risk.” JCI Insight, vol. 3, no. 4, 2018, e98045.
[14] Phillipson BE, et al. “Reduction of plasma lipids, lipoproteins, and apoproteins by dietary fish oils in patients with hypertriglyceridemia.” New England Journal of Medicine, vol. 312, no. 19, 1985, pp. 1210-1216.
[15] Riches FM, et al. “Apolipoprotein B signal peptide and apolipoprotein E genotypes as determinants of the hepatic secretion of VLDL apoB in obese men.” Journal of Lipid Research, vol. 39, no. 9, 1998, pp. 1752-1758.
[16] Abul-Husn NS, et al. “A Protein-Truncating HSD17B13 Variant and Protection from Chronic Liver Disease.” New England Journal of Medicine, vol. 378, no. 12, 2018, pp. 1096-1106.
[17] Chakravarthy MV, et al. “New” hepatic fat activates PPARα to maintain glucose, lipid, and cholesterol homeostasis.” Cell Metabolism, vol. 1, no. 5, 2005, pp. 309-322.
[18] Stachowska E, et al. “Apolipoprotein E4 allele is associated with substantial changes in the plasma lipids and hyaluronic acid content in patients with nonalcoholic fatty liver disease.” Journal of Physiology and Pharmacology, vol. 64, no. 6, 2013, pp. 711-717.
[19] Mahdessian H, et al. “TM6SF2 is a regulator of liver fat metabolism influencing triglyceride secretion and hepatic lipid droplet content.” Proceedings of the National Academy of Sciences, vol. 111, no. 24, 2014, pp. 8913-8918.
[20] Chen Y, et al. “Genome-wide association meta-analysis identifies 17 loci associated with nonalcoholic fatty liver disease.” Nature Genetics, vol. 55, no. 10, 2023, pp. 1776-1786.