[Research progress on regulation of N6-adenylate methylation modification in lipid metabolism disorders].

Lipid metabolism is a complex physiological process, which is closely related to nutrient regulation, hormone balance and endocrine function. It involves the interactions of multiple factors and signal transduction pathways. Lipid metabolism disorder is one of the main mechanisms to induce a variety of diseases, such as obesity, diabetes, non-alcoholic fatty liver disease, hepatitis, hepatocellular carcinoma and their complications. At present, more and more studies have found that the "dynamic modification" of N6-adenylate methylation (m6A) on RNA represents a new "post-transcriptional" regulation mode. m6A methylation modification can occur in mRNA, tRNA, ncRNA, etc. Its abnormal modification can regulate gene expression changes and alternative splicing events. Many latest references have reported that m6A RNA modification is involved in the epigenetic regulation of lipid metabolism disorder. Based on the major diseases induced by lipid metabolism disorders, we reviewed the regulatory roles of m6A modification in the occurrence and development of those diseases. These overall findings inform further in-depth investigations of the underlying molecular mechanisms regarding the pathogenesis of lipid metabolism disorders from the perspective of epigenetics, and provide reference for health prevention, molecular diagnosis and treatment of related diseases.

A cohort study on risk factors of high-density lipoprotein cholesterol hypolipidemia among urban Chinese adults.

BACKGROUND: High-density lipoprotein cholesterol (HDL-C) hypolipidemia, a major type of dyslipidemia, has been associated with many kinds of diseases, such as stroke, coronary heart disease, obesity and diabetes, and has displayed an increasing prevalence in China. This study explores the risk factors of HDL-C hypolipidemia and makes recommendations for controlling and preventing HDL-C hypolipidemia and the diseases caused by it. METHODS: Using a retrospective cohort study design, 26,863 urban adults without dyslipidemia, diabetes, cardiovascular and cerebrovascular diseases, hepatosis, renal insufficiency and thyroid diseases were enrolled in the study between 2010 and 2015. Data on each individual were collected at the 2010 baseline year and at a follow-up medical check. A Cox regression model was constructed to evaluate the influence of potential risk factors on the outcome event- HDL-C hypolipidemia. RESULTS: The incidence of HDL-C hypolipidemia was 5.7% (1531/26863). Sex, age, body mass index (BMI), HDL-C, triglyceride (TG) and urea nitrogen (UN) were significant risk factors of HDL-C hypolipidemia. Men were more likely to develop HDL-C hypolipidemia than women during follow-up medical checks (HR = 1.258, P = 0.014). The incidence of HDL-C hypolipidemia in the over 65 years old group was higher than that of the ≤65 age group (HR = 1.276, P = 0.009). The incidence of HDL-C hypolipidemia increased with increasing BMI (HR = 1.030, P = 0.002), TG (HR = 1.321, P = 0.001) and UN (HR = 1.054, P = 0.019), while falling with increasing HDL-C in the baseline year (HR = 0.002, P < 0.001). CONCLUSIONS: Men, aged over 65, with high BMI were at the highest risk of developing HDL-C hypolipidemia. Measures should be taken to prevent HDL-C hypolipidemia even for healthy urban adults whose blood biochemical indicators were in the normal range when their level of TG, UN and HDL-C are closed to the border of the normal value range.

Familial combined hypolipidemia: angiopoietin-like protein-3 deficiency.

PURPOSE OF REVIEW: Angiopoietin-like protein-3 (ANGPTL3) is emerging as a key player in lipoprotein transport with an expanding role on fatty acid and glucose metabolism. Its deficiency is associated with a favorable metabolic profile. The present review will highlight the recent understanding of metabolic and cardiovascular consequences of ANGPTL3 inactivation by considering both genetic and pharmacological investigations. RECENT FINDINGS: Experimental studies have further illustrated the complex interplay between ANGPTL3 and ANGPTL4-8 in orchestrating lipid transport in different nutritional status. Individuals with familial combined hypolipidemia due to homozygous loss-of-function mutations in ANGPTL3 gene showed improved metabolism of triglyceride-rich lipoproteins during fasting and postprandial state and increased fatty acid oxidation and insulin sensitivity. Moreover, mendelian randomizations studies demonstrated that partial ANGPTL3 deficiency associates with reduced risk of atherosclerotic cardiovascular events and, eventually, diabetes mellitus. Finally, inactivation of ANGPTL3, using either a specific mAb or antisense oligonucleotide, was reported to reduce plasma levels of atherogenic lipoprotein in humans and improve hepatic fat infiltration in animal models. SUMMARY: Human and animal studies have further dissected the complex role of ANGPTL3 in the regulation of energy substrate metabolism. Moreover, genetic and pharmacological investigations have convincingly indicated that the inactivation of ANGPTL3 may be a very promising strategy to treat atherogenic metabolic disorders.

The evolution of genetic-based risk scores for lipids and cardiovascular disease.

PURPOSE OF REVIEW: With improved next-generation sequencing technology, open-access genetic databases and increased awareness of complex trait genetics, we are entering a new era of risk assessment in which genetic-based risk scores (GRSs) will play a clinical role. We review the concepts underlying polygenic models of disease susceptibility and challenges in clinical implementation. RECENT FINDINGS: Polygenic risk scores are currently used in genetic research on dyslipidemias and cardiovascular disease (CVD). Although the underlying principles for constructing polygenic scores for lipids are established, the lack of consensus on which score to use is indicated by the large number - about 50 - that have been published. Recently, large-scale polygenic scores for CVD appear to afford superior risk prediction compared to small-scale scores. Despite the potential benefits of GRSs, certain biases towards ethnicity and sex need to be worked through. SUMMARY: We are on the verge of clinical application of GRSs to provide incremental information on dyslipidemia and CVD risk above and beyond traditional clinical variables. Additional work is required to develop a consensus of how such scores will be constructed and measured in a validated manner, as well as clinical indications for their use.

The biochemical and genetic diagnosis of lipid disorders.

PURPOSE OF REVIEW: To examine recent advances in our knowledge on the diagnosis of lipid disorders. RECENT FINDINGS: Fasting values above the 99th percentile for direct LDL-cholesterol (LDL-C), lipoprotein(a), and triglycerides are greater than 225 mg/dl, greater than 160 mg/dl, and greater than 500 mg/dl (>5.82, >394, and >5.65 mmol/l), respectively, whereas such values for plasma lathosterol, ß-sitosterol, and cholestanol are greater than 8.0, 8.0, and 5.0 mg/l (>0.021, 0.019, and 0.013 mmol/l), respectively. Values below the first percentile for LDL-C are less than 40 mg/dl (<1.03 mmol/l) and for HDL-cholesterol (HDL-C) less than 25 mg/dl (<0.65 mmol/l) in men and less than 30 mg/dl (<0.78 mmol/l) in women, respectively. The above values can predispose to premature CVD, pancreatitis, neurologic disease, and kidney failure, and may be associated with monogenic lipid disorders. In the absence of secondary causes including diabetes or kidney, liver, or thyroid disease, consideration should be given to sequencing the following genes: ABCA1, ABCG5, ABCG8, APOA1, APOA5, APOB, APOC2, APOE, CETP, CYP27A1, GPIHBP1, LCAT, LDLR, LDLRAP1, LIPA, LIPC, LMF1, LPL, MTTP, PCSK9, SCARB1, and STAP1. SUMMARY: Recent data indicate that secondary causes and a wider range of conditions need to be considered in identifying the underlying causes of hypercholesterolemia, hypertriglyceridemia, hyperalphalipoproteinemia, hypobetalipoproteinemia, and HDL deficiency. Identifying such disorders allows for a more precise assessment of prognosis and the formulation of optimal therapy.

Intestinal Failure and Aberrant Lipid Metabolism in Patients With DGAT1 Deficiency.

BACKGROUND & AIMS: Congenital diarrheal disorders are rare inherited intestinal disorders characterized by intractable, sometimes life-threatening, diarrhea and nutrient malabsorption; some have been associated with mutations in diacylglycerol-acyltransferase 1 (DGAT1), which catalyzes formation of triacylglycerol from diacylglycerol and acyl-CoA. We investigated the mechanisms by which DGAT1 deficiency contributes to intestinal failure using patient-derived organoids. METHODS: We collected blood samples from 10 patients, from 6 unrelated pedigrees, who presented with early-onset severe diarrhea and/or vomiting, hypoalbuminemia, and/or (fatal) protein-losing enteropathy with intestinal failure; we performed next-generation sequencing analysis of DNA from 8 patients. Organoids were generated from duodenal biopsies from 3 patients and 3 healthy individuals (controls). Caco-2 cells and patient-derived dermal fibroblasts were transfected or transduced with vectors that express full-length or mutant forms of DGAT1 or full-length DGAT2. We performed CRISPR/Cas9-guided disruption of DGAT1 in control intestinal organoids. Cells and organoids were analyzed by immunoblot, immunofluorescence, flow cytometry, chromatography, quantitative real-time polymerase chain reaction, and for the activity of caspases 3 and 7. RESULTS: In the 10 patients, we identified 5 bi-allelic loss-of-function mutations in DGAT1. In patient-derived fibroblasts and organoids, the mutations reduced expression of DGAT1 protein and altered triacylglycerol metabolism, resulting in decreased lipid droplet formation after oleic acid addition. Expression of full-length DGAT2 in patient-derived fibroblasts restored formation of lipid droplets. Organoids derived from patients with DGAT1 mutations were more susceptible to lipid-induced cell death than control organoids. CONCLUSIONS: We identified a large cohort of patients with congenital diarrheal disorders with mutations in DGAT1 that reduced expression of its product; dermal fibroblasts and intestinal organoids derived from these patients had altered lipid metabolism and were susceptible to lipid-induced cell death. Expression of full-length wildtype DGAT1 or DGAT2 restored normal lipid metabolism in these cells. These findings indicate the importance of DGAT1 in fat metabolism and lipotoxicity in the intestinal epithelium. A fat-free diet might serve as the first line of therapy for patients with reduced DGAT1 expression. It is important to identify genetic variants associated with congenital diarrheal disorders for proper diagnosis and selection of treatment strategies.

Genetic risk scores in lipid disorders.

PURPOSE OF REVIEW: Extensive work has gone into understanding the genetics of cardiovascular disease (CVD) and implicating genes involved in hyperlipidaemia. Translation into routine practise involves using genetic risk scores (GRS) to identify high-risk individuals in the general population. Some of these risk scores are beginning to disentangle the complex nature of CVD and inherited dyslipidaemias. RECENT FINDINGS: GRS of varying complexity have been used to identify high-risk groups of patients with polygenic CVD including some individuals with risk equivalent to monogenic disease. In phenotypic familial hypercholesterolaemia a six or 12 gene lipid GRS may identify polygenic cases that comprise up to 50% of cases. In high triglyceride syndromes including even cases of familial chylomicronaemia syndrome more than 80% of cases are polygenic and not even associated with rare variants. In both familial hypercholesterolaemia and familial chylomicronaemia syndrome individuals with polygenic disease have a lower risk than those with monogenic disease. SUMMARY: GRS show promise in identifying individuals with high risks of CVD. They have a close relationship with imaging markers. It is unclear whether GRS, imaging or both will be used to identify individuals at high risk of future events.

RNA-targeted therapeutics for lipid disorders.

PURPOSE OF REVIEW: To summarize recent developments in the field of RNA-directed therapeutics targeting lipid disorders that are not effectively managed. RECENT FINDINGS: Despite a number of approved therapies for lipid disorders, significant unmet needs are present in treating persistently elevated LDL-cholesterol, remnant-cholesterol, triglycerides and lipoprotein(a) [Lp(a)]. Small molecules and antibodies are effective modalities, but they are unable to adequately treat many patients with abnormal lipid parameters. Targeting mRNA with oligonucleotides to prevent protein translation is a relatively novel method to reduce circulating atherogenic lipoproteins. Small inhibiting RNA (siRNA) molecules targeting proprotein convertase subtilisin kexin type 9 to reduce LDL-C, and antisense oligonucleotides (ASO) targeting apolipoprotein C-III (apoC-III) to reduce triglycerides, angiopoietin-like 3 (ANGPTL3) to reduce LDL-C and triglycerides and apolipoprotein(a) (LPA) to reduce Lp(a) are currently in or just completed phase 1-3 trials. Fundamental differences exist in chemistry, delivery and mechanism of action of siRNA and ASOs. SUMMARY: Novel RNA therapeutics are poised to provide highly potent, specific and effective therapies to reduce atherogenic lipoproteins. As these compounds are approved, clinicians will be able to choose from a broad armamentarium to treat nearly all patients to acceptable goals in order to reduce risk of cardiovascular disease and events.

Identification and Characterization of CircRNAs of Two Pig Breeds as a New Biomarker in Metabolism-Related Diseases.

BACKGROUND/AIMS: CircRNAs, as miRNA sponges, participate in many important biological processes. However, it remains unclear whether circRNAs can regulate lipid metabolism. This paper aims to study the molecular mechanism of fat deposition and provide useful information for the prevention and therapy of lipid metabolism-related diseases. METHODS: CircRNA sequencing was performed to investigate the expression of circRNAs in the subcutaneous adipose tissues of Large White pig and Laiwu pig. The expression of circRNAs was further validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Furthermore, circRNA-microRNAs (miRNA)-mRNA interaction networks were constructed using bioinformatics tools. In addition, GO and KEGG enrichment analyses were performed for the target genes of circRNAs. RESULTS: In the subcutaneous adipose tissue of Laiwu pig, 70 up-regulated circRNAs and 205 down-regulated circRNAs were identified. Two circRNAs (up-regulated circRNA_26852 and down-regulated circRNA_11897), the expressions of which were confirmed by qRT-PCR, were selected for subsequent analysis. CircRNA-miRNA-mRNA interaction networks were constructed for circRNA_26852 and its target genes as well as circRNA_11897 and its target genes. GO and KEGG enrichment analyses reveal that the target genes of circRNA_26852 and circRNA_11897 are enriched in pathways related to adipocyte differentiation and lipid metabolism, as well as in disease-related pathways. CONCLUSIONS: In this study, circRNA sequencing and bioinformatics technique were used to analyze, for the first time, the expression of circRNAs in the subcutaneous adipose tissues of Large White pig and Laiwu pig. It is inferred that circRNAs might regulate adipogenic differentiation and lipid metabolism. The results provide a theoretical basis for further study on fat deposition mechanism and provide potential therapy targets for metabolism-related diseases.

Does lifestyle contribute to disease severity in patients with inherited lipid disorders?

PURPOSE OF REVIEW: Patients with familial hypercholesterolemia, familial combined hyperlipidemia and hyperlipoprotein(a) are at high cardiovascular risk. Increasing evidence suggest that lifestyle-related risk factors such as physical inactivity, and poor diet quality could influence cardiovascular risk in these patients. Our objective is to review the evidence that supports the role of lifestyle-related factors in the prediction of cardiovascular risk in patients with inherited lipid disorders. RECENT FINDINGS: Recent studies have shown that smoking, a poor diet quality, physical inactivity, fitness levels, abdominal obesity, insulin resistance, and type 2 diabetes were associated with the presence of atherosclerosis and long-term cardiovascular outcomes in patients with familial hypercholesterolemia. Recent evidence also suggest that managing other cardiovascular risk factors such as cholesterol levels, obesity, glycemic control, blood pressure, smoking, physical inactivity, and diet quality could reduce long-term cardiovascular risk associated with hyperlipoprotein(a). Whether targeting these risk factors could ultimately decrease cardiovascular risk in these patients remains unknown. SUMMARY: Although reducing the number of atherogenic apolipoprotein-B containing particle with lipid-lowering therapy represents the cornerstone of treatment of patients with inherited lipid disorders, lifestyle-related risk factors such as physical inactivity and poor diet quality need to be targeted for the optimal management of these high-risk patients.

A Comparison Study of Fixed and Mixed Effect Models for Gene Level Association Studies of Complex Traits.

In association studies of complex traits, fixed-effect regression models are usually used to test for association between traits and major gene loci. In recent years, variance-component tests based on mixed models were developed for region-based genetic variant association tests. In the mixed models, the association is tested by a null hypothesis of zero variance via a sequence kernel association test (SKAT), its optimal unified test (SKAT-O), and a combined sum test of rare and common variant effect (SKAT-C). Although there are some comparison studies to evaluate the performance of mixed and fixed models, there is no systematic analysis to determine when the mixed models perform better and when the fixed models perform better. Here we evaluated, based on extensive simulations, the performance of the fixed and mixed model statistics, using genetic variants located in 3, 6, 9, 12, and 15 kb simulated regions. We compared the performance of three models: (i) mixed models that lead to SKAT, SKAT-O, and SKAT-C, (ii) traditional fixed-effect additive models, and (iii) fixed-effect functional regression models. To evaluate the type I error rates of the tests of fixed models, we generated genotype data by two methods: (i) using all variants, (ii) using only rare variants. We found that the fixed-effect tests accurately control or have low false positive rates. We performed simulation analyses to compare power for two scenarios: (i) all causal variants are rare, (ii) some causal variants are rare and some are common. Either one or both of the fixed-effect models performed better than or similar to the mixed models except when (1) the region sizes are 12 and 15 kb and (2) effect sizes are small. Therefore, the assumption of mixed models could be satisfied and SKAT/SKAT-O/SKAT-C could perform better if the number of causal variants is large and each causal variant contributes a small amount to the traits (i.e., polygenes). In major gene association studies, we argue that the fixed-effect models perform better or similarly to mixed models in most cases because some variants should affect the traits relatively large. In practice, it makes sense to perform analysis by both the fixed and mixed effect models and to make a comparison, and this can be readily done using our R codes and the SKAT packages.

Cardiac overexpression of perilipin 2 induces dynamic steatosis: prevention by hormone-sensitive lipase.

Cardiac intracellular lipid accumulation (steatosis) is a pathophysiological phenomenon observed in starvation and diabetes mellitus. Perilipin 2 (PLIN2) is a lipid droplet (LD)-associated protein expressed in nonadipose tissues, including the heart. To explore the pathophysiological function of myocardial PLIN2, we generated transgenic (Tg) mice by cardiac-specific overexpression of PLIN2. Tg hearts showed accumulation of numerous small LDs associated with mitochondrial chains and high cardiac triacylglycerol (TAG) content [8-fold greater than wild-type (WT) mice]. Despite massive steatosis, cardiac uptake of glucose, fatty acids and VLDL, systolic function, and expression of metabolic genes were comparable in the two genotypes, and no morphological changes were observed by electron microscopy in the Tg hearts. Twenty-four hours of fasting markedly reduced steatosis in Tg hearts, whereas WT mice showed accumulation of LDs. Although activity of adipose triglyceride lipase in heart homogenate was comparable between WT and Tg mice, activity of hormone-sensitive lipase (HSL) was 40-50% less in Tg than WT mice under both feeding and fasting conditions, suggesting interference of PLIN2 with HSL. Mice generated through crossing of PLIN2-Tg mice and HSL-Tg mice showed cardiac-specific HSL overexpression and complete lack of steatosis. The results suggest that cardiac PLIN2 plays an important pathophysiological role in the development of dynamic steatosis and that the latter was prevented by upregulation of intracellular lipases, including HSL.

Monogenic neurological disorders of sphingolipid metabolism.

Sphingolipids comprise a wide variety of molecules containing a sphingoid long-chain base that can be N-acylated. These lipids are particularly abundant in the central nervous system, being membrane components of neurons as well as non-neuronal cells. Direct evidence that these brain lipids play critical functions in brain physiology is illustrated by the dramatic consequences of genetic disturbances of their metabolism. Inherited defects of both synthesis and catabolism of sphingolipids are now identified in humans. These monogenic disorders are due to mutations in the genes encoding for the enzymes that catalyze either the formation or degradation of simple sphingolipids such as ceramides, or complex sphingolipids like glycolipids. They cause varying degrees of central nervous system dysfunction, quite similarly to the neurological disorders induced in mice by gene disruption of the corresponding enzymes. Herein, the enzyme deficiencies and metabolic alterations that underlie these diseases are reviewed. Their possible pathophysiological mechanisms and the functions played by sphingolipids one can deduce from these conditions are discussed. This article is part of a Special Issue entitled Brain Lipids.

Hepatitis B virus inhibits apolipoprotein A5 expression through its core gene.

BACKGROUND: Hepatitis B virus (HBV) infection causes lipid metabolism disorders. Apolipoprotein A5 (ApoA5) is a new apolipoprotein family member that plays an important role in the regulation of lipid metabolism. The present study was to investigate the impact of HBV on ApoA5 expression and its regulatory mechanism. METHODS: Reverse transcription polymerase chain reaction (RT-PCR) and western blotting were used to measure ApoA5 mRNA and protein expression in HepG2 and HepG2.2.15 cells. Enzyme-linked immunosorbent assay (ELISA) was used to measure the serum ApoA5 levels in healthy individuals and HBV patients. HBV infectious clone pHBV1.3 or individual plasmids expressing the HBV genome was cotransfected with the ApoA5 promoter pGL3-Apo5-LUC plasmid into HepG2 cells to assess the luciferase activity. RT-PCR and western blotting methods were used to detect Apo5 mRNA and protein expression, respectively. RESULTS: The ApoA5 mRNA and protein expression levels were decreased in HepG2.2.15 cells compared with the control HepG2 cells. The serum ApoA5 levels were 196.4 ± 28.7 µg/L in the healthy individuals and 104.5 ± 18.3 µg/L in the HBV patients, statistical analysis showed that the ApoA5 levels were significantly lower in HBV patients than in the healthy individuals (P < 0.05). pHBV1.3 and its core gene inhibited ApoA5 promoter activity and mRNA and protein expression in HepG2 cells. CONCLUSION: HBV inhibits ApoA5 expression at both the transcriptional and translational levels through its core gene.

Association of apolipoprotein E polymorphism with plasma lipid disorders, independent of obesity-related traits in Vietnamese children.

BACKGROUND: The dyslipidemia associated with obesity plays a major role in the development of atherosclerosis and cardiovascular disease. Dyslipidemia in childhood can progress in adult stage. APOE is one of the most important genes that regulate plasma lipid transport and clearance. The study aimed to assess whether the common APOE polymorphism is associated with lipid profiles and dyslipidemia, and it could be modulated by obesity-related traits (body mass index, waist circumference, hip circumference, and waist-to-hip ratio) in Vietnamese children. METHODS: A case-control study was designed including 249 cases with dyslipidemia and 600 controls without dyslipidemia. Dyslipidemia is defined as elevated total or low-density lipoprotein (LDL) cholesterol levels, or low levels of high-density lipoprotein (HDL) cholesterol. Genotype for APOE polymorphism (rs7412 and rs429358) was determined by the polymerase chain reaction and restriction fragment length polymorphism method. The association of APOE genotypes with plasma lipid disorders was tested by binary logistic regression analysis, taking into account the confounding factors of age, sex, residence, province and obesity-related traits. RESULTS: In comparison with ε3/ε3 carriers, the ε4 carriers had the highest concentration of serum TC and LDL-C in cases and controls (P ≤ 0.001), while ε2 carriers had the lowest. Carriers without TT haplotype had higher serum TC than those with TT haplotype. The ε4 carriers had higher hypoalphalipoproteinemia risk than ε3/ε3 carriers (OR = 2.78, P = 0.02) before and after adjustment for age, gender, residence and obesity-related traits. CONCLUSIONS: The study suggested that the APOE genotype and haplotype significantly associated with plasma TC and LDL-C level in Vietnamese children. The association of APOE genotype with hypoalphalipoproteinemia was independent of obesity-related traits.

Precursor of ether phospholipids is synthesized by a flavoenzyme through covalent catalysis.

The precursor of the essential ether phospholipids is synthesized by a peroxisomal enzyme that uses a flavin cofactor to catalyze a reaction that does not alter the redox state of the substrates. The enzyme crystal structure reveals a V-shaped active site with a narrow constriction in front of the prosthetic group. Mutations causing inborn ether phospholipid deficiency, a very severe genetic disease, target residues that are part of the catalytic center. Biochemical analysis using substrate and flavin analogs, absorbance spectroscopy, mutagenesis, and mass spectrometry provide compelling evidence supporting an unusual mechanism of covalent catalysis. The flavin functions as a chemical trap that promotes exchange of an acyl with an alkyl group, generating the characteristic ether bond. Structural comparisons show that the covalent versus noncovalent mechanistic distinction in flavoenzyme catalysis and evolution relies on subtle factors rather than on gross modifications of the cofactor environment.

[Development of lipids and carbohydrates metabolism disorders caused by drinkable water with high content of chlorine organic compounds].

Evaluation of effects caused by environmental peroral exposure to chlorine organic compounds revealed that individuals with AG variation of HTR2A gene are a community with increased sensitivity to chloroform and a risk group for lipid and carbohydrates metabolism disorders. Individual risk of endocrine disorders (ICD: E67.8 excessive nutrition and E66.0 obesity) in these individuals is higher than in general population exposed to chloroform at residence (HQ1.72). Serum serotonin level, that is functionally connected with HTR2A gene, is 1.3 times lower vs. the reference group value.

Apolipoprotein E isoforms and lipoprotein metabolism.

Apolipoprotein (apo) E is a 299-residue protein which functions as a key regulator of plasma lipid levels. Human apoE exists as three common isoforms and the parent form, apoE3, operates optimally in promoting clearance of triglyceride (TG)-rich lipoproteins and is associated with normal plasma lipid levels. This result occurs because apoE3 possesses both the requisite lipid-binding ability and affinity for the low density lipoprotein receptor (LDLR) to mediate appropriate lipolytic processing and endocytosis of TG-rich lipoprotein remnant particles. ApoE2 which differs from apoE3 by the single amino acid substitution Arg158Cys located near the LDLR recognition site exhibits impaired binding to the receptor and an inability to promote clearance of TG-rich lipoprotein remnant particles; this isoform is associated with Type-III hyperlipoproteinemia. ApoE4 which differs from apoE3 by the single amino acid substitution Cys112Arg is also associated with dyslipidemia although binding of this isoform to the LDLR is unaffected. The amino acid substitution affects the organization and stability of both the N-terminal helix bundle domain and separately folded C-terminal domain so that apoE4 has enhanced lipid binding ability. As a consequence, apoE4 binds better than apoE3 to the surface of very low density lipoprotein (VLDL) particles and impairs their lipolytic processing in the circulation so that apoE4 is associated with a more pro-atherogenic lipoprotein-cholesterol distribution (higher VLDL-cholesterol/high density lipoprotein-cholesterol ratio). This review summarizes current understanding of the structural differences between apoE2, apoE3, and apoE4, and the molecular mechanisms responsible for the alterations in lipoprotein metabolism resulting from this polymorphism of apoE. Detailed knowledge of how expression of structurally distinct apoE variants modifies lipoprotein metabolism provides a basis for developing ways to manipulate the functionality of apoE in vivo.

DEAD-Box Helicase 17 exacerbates non-alcoholic steatohepatitis via transcriptional repression of cyp2c29, inducing hepatic lipid metabolism disorder and eliciting the activation of M1 macrophages.

OBJECTIVE: Our study was to elucidate the role of RNA helicase DEAD-Box Helicase 17 (DDX17) in NAFLD and to explore its underlying mechanisms. METHODS: We created hepatocyte-specific Ddx17-deficient mice aim to investigate the impact of Ddx17 on NAFLD induced by a high-fat diet (HFD) as well as methionine and choline-deficient l-amino acid diet (MCD) in adult male mice. RNA-seq and lipidomic analyses were conducted to depict the metabolic landscape, and CUT&Tag combined with chromatin immunoprecipitation (ChIP) and luciferase reporter assays were conducted. RESULTS: In this work, we observed a notable increase in DDX17 expression in the livers of patients with NASH and in murine models of NASH induced by HFD or MCD. After introducing lentiviruses into hepatocyte L02 for DDX17 knockdown or overexpression, we found that lipid accumulation induced by palmitic acid/oleic acid (PAOA) in L02 cells was noticeably weakened by DDX17 knockdown but augmented by DDX17 overexpression. Furthermore, hepatocyte-specific DDX17 knockout significantly alleviated hepatic steatosis, inflammatory response and fibrosis in mice after the administration of MCD and HFD. Mechanistically, our analysis of RNA-seq and CUT&Tag results combined with ChIP and luciferase reporter assays indicated that DDX17 transcriptionally represses Cyp2c29 gene expression by cooperating with CCCTC binding factor (CTCF) and DEAD-Box Helicase 5 (DDX5). Using absolute quantitative lipidomics analysis, we identified a hepatocyte-specific DDX17 deficiency that decreased lipid accumulation and altered lipid composition in the livers of mice after MCD administration. Based on the RNA-seq analysis, our findings suggest that DDX17 could potentially have an impact on the modulation of lipid metabolism and the activation of M1 macrophages in murine NASH models. CONCLUSION: These results imply that DDX17 is involved in NASH development by promoting lipid accumulation in hepatocytes, inducing the activation of M1 macrophages, subsequent inflammatory responses and fibrosis through the transcriptional repression of Cyp2c29 in mice. Therefore, DDX17 holds promise as a potential drug target for the treatment of NASH.

Secreted Frizzled-Related Protein 5 Mediates Wnt5a Expression in Microcystin-Leucine-Arginine-Induced Liver Lipid Metabolism Disorder in Mice.

Objective: Microcystin-leucine-arginine (MC-LR) exposure induces lipid metabolism disorders in the liver. Secreted frizzled-related protein 5 (SFRP5) is a natural antagonist of winglesstype MMTV integration site family, member 5A (Wnt5a) and an anti-inflammatory adipocytokine. In this study, we aimed to investigate whether MC-LR can induce lipid metabolism disorders in hepatocytes and whether SFRP5, which has anti-inflammatory effects, can alleviate the effects of hepatic lipid metabolism by inhibiting the Wnt5a/Jun N-terminal kinase (JNK) pathway. Methods: We exposed mice to MC-LR in vivo to induce liver lipid metabolism disorders. Subsequently, mouse hepatocytes that overexpressed SFRP5 or did not express SFRP5 were exposed to MC-LR, and the effects of SFRP5 overexpression on inflammation and Wnt5a/JNK activation by MC-LR were observed. Results: MC-LR exposure induced liver lipid metabolism disorders in mice and significantly decreased SFRP5 mRNA and protein levels in a concentration-dependent manner. SFRP5 overexpression in AML12 cells suppressed MC-LR-induced inflammation. Overexpression of SFRP5 also inhibited Wnt5a and phosphorylation of JNK. Conclusion: MC-LR can induce lipid metabolism disorders in mice, and SFRP5 can attenuate lipid metabolism disorders in the mouse liver by inhibiting Wnt5a/JNK signaling.