AIM To evaluate the impact of the Glu167Lys(E167K) transmembrane 6 superfamily member 2(TM6SF2) variant on the biochemical and morphologic expression of liver lesions in human immunodeficiency virus(HIV)/hepatitis C v...AIM To evaluate the impact of the Glu167Lys(E167K) transmembrane 6 superfamily member 2(TM6SF2) variant on the biochemical and morphologic expression of liver lesions in human immunodeficiency virus(HIV)/hepatitis C virus(HCV) co-infected patients.METHODS The study comprised 167 consecutive patients with HIV/HCV coinfection and biopsy-proven chronic hepatitis. A pathologist graded liver fibrosis and necroinflammation using the Ishak scoring system, and steatosis using Kleiner's scoring system. Patients were genotyped for TM6SF2 E167K(rs58542926) by real-time Polymerase chain reaction. The 167 patients, 35 therapy-naive and 132 receiving ART, were prevalently males(73.6%), the median age was 40.7 years and the immunological condition good(median CD4+ cells/mm3 = 505.5).RESULTS The 17 patients with the TM6SF2 E167 K variant, compared with the 150 with TM6SF2-E/E, showed higher AST(P = 0.02) and alanine aminotransferase(P = 0.02) and higher fibrosis score(3.1 ± 2.0 vs 2.3 ± 1.5, P = 0.05). In a multivariate analysis, TM6SF2 E167 K was independently associated with severe fibrosis. The same analysis showed that HCV-genotype 3, present in 42.2% of patients was an independent predictor of severe steatosis. The association of TM6SF2 E167 K with severe steatosis, absent for the whole group of 167 patients, was re-evaluated separately for HCVgenotype 3 and non-3 patients: No factor was independently associated with severe steatosis in the HCV-genotype-3 subgroup, whereas an independent association was observed between severe steatosis and TM6SF2 E167 K in non-3 HCV genotypes. No association between the TM6SF2 E167 K variant and severe liver necroinflammation was observed.CONCLUSION In HIV/HCV coinfection the TM6SF2 E167 K variant is an independent predictor of severe fibrosis, but appears to be independently associated with severe steatosis only for patients with a non-3 HCV genotype.展开更多
BACKGROUND The lack of effective pharmacotherapies for nonalcoholic fatty liver disease(NAFLD)is mainly attributed to insufficient research on its pathogenesis.The pathogenesis of TM6SF2-efficient NAFLD remains unclea...BACKGROUND The lack of effective pharmacotherapies for nonalcoholic fatty liver disease(NAFLD)is mainly attributed to insufficient research on its pathogenesis.The pathogenesis of TM6SF2-efficient NAFLD remains unclear,resulting in a lack of therapeutic strategies for TM6SF2-deficient patients.AIM To investigate the role of TM6SF2 in fatty acid metabolism in the context of fatty liver and propose possible therapeutic strategies for NAFLD caused by TM6SF2 deficiency.METHODS Liver samples collected from both NAFLD mouse models and human participants(80 cases)were used to evaluate the expression of TM6SF2 by using western blotting,immunohistochemistry,and quantitative polymerase chain reaction.RNA-seq data retrieved from the Gene Expression Omnibus database were used to confirm the over-expression of TM6SF2.Knockdown and overexpression of TM6SF2 were performed to clarify the mechanistic basis of hepatic lipid accumulation in NAFLD.MK-4074 administration was used as a therapeutic intervention to evaluate its effect on NAFLD caused by TM6SF2 deficiency.RESULTS Hepatic TM6SF2 levels were elevated in patients with NAFLD and NAFLD mouse models.TM6SF2 overexpression can reduce hepatic lipid accumulation,suggesting a protective role for TM6SF2 in a high-fat diet(HFD).Downregulation of TM6SF2,simulating the TM6SF2 E167K mutation condition,increases intracellular lipid deposition due to dysregulated fatty acid metabolism and is characterized by enhanced fatty acid uptake and synthesis,accompanied by impaired fatty acid oxidation.Owing to the potential effect of TM6SF2 deficiency on lipid metabolism,the application of an acetyl-CoA carboxylase inhibitor(MK-4074)could reverse the NAFLD phenotypes caused by TM6SF2 deficiency.CONCLUSION TM6SF2 plays a protective role in the HFD condition;its deficiency enhanced hepatic lipid accumulation through dysregulated fatty acid metabolism,and MK-4074 treatment could alleviate the NAFLD phenotypes caused by TM6SF2 deficiency.展开更多
Nonalcoholic fatty liver disease(NAFLD)is one of the most common causes of liver dysfunction worldwide,and its prevalence is highly associated with genetic susceptibility.The transmembrane 6 superfamily member 2(TM6SF...Nonalcoholic fatty liver disease(NAFLD)is one of the most common causes of liver dysfunction worldwide,and its prevalence is highly associated with genetic susceptibility.The transmembrane 6 superfamily member 2(TM6SF2)E167K variant represents a general genetic determinant of hepatic triglyceride content and lobular inflammation,and its presence appears to be directly involved in the pathogenesis and development of NAFLD.Although this variant appears to be a novel powerful modifier in the development of NAFLD,whether it is associated with an increased risk of NAFLD-refated liver fibrosis and hepatocellular carcinoma(HCC)remains to be determined.The aim of this review is to describe the functions of the TM6SF2 E167K variant and its association with NAFLD,with particular emphasis on the underlying mechanisms of its role in the development and progression of NAFLD.Additionally,the links between the TM6SF2 E167K variant and NAFLD-related liver fibrosis and HCC will be discussed.展开更多
Background and Aims:Accumulated evidence has shown that chronic liver inflammation is one of the main risks of hepatocellular carcinoma(HCC),and E167K variant of the transmembrane 6 superfamily member 2(TM6SF2)plays a...Background and Aims:Accumulated evidence has shown that chronic liver inflammation is one of the main risks of hepatocellular carcinoma(HCC),and E167K variant of the transmembrane 6 superfamily member 2(TM6SF2)plays an important role in the progression of chronic liver diseases and HCC.The aim of this study was to explore effects of the TM6SF2 E167K variant on expression of the inflammatory cytokines TNF-cα,IL-2,IL-6 and IL-8 in the HCC cell line HEPA 1-6.Methods:HEPA 1-6 cells were infected with lentivirus containing either the TM6SF2 E167K variant or TM6SF2 wildtype,or control plasmids.Quantitative real-time polymerase chain reaction(qRT-PCR)and western blotting were conducted to analyze the expression of the inflammatory cytokines TNF-α,IL-2,IL-6 and IL-8.A t-test was used for statistical analysis.Results:Compared with the control group and TM6SF2 overexpression group,the relative expression of IL-2 and IL-6 mRNAs were significantly elevated in the TM6SF2 E167K overexpression group(p<0.05).The relative mRNA expression of IL-8 in theTM6SF2 and TM6SF2 E167K overexpression groups were increased compared to the control group(p<0.05).No obvious differences were observed for the expression of TNF-αin each group.The expression of TNF-α,IL-2,IL-6 and IL-8 that was tested by western blotting showed the same trends as the qRT-PCR results.Conclusions:In conclusion,the E167K variant of theTM6SF2 gene could promote the expression of inflammatory cytokines IL-2 and IL-6 in HEPA 1-6 cells,suggesting that the TM6SF2 E167K variant may accelerate the progression of HCC.展开更多
The transmembrane 6 superfamily member 2(TM6SF2)gene E167K variant(rs58542926)was identified by exome-wide as-sociation study as a nonsynonymous single nucleotide poly-morphism associated with nonalcoholic fatty liver...The transmembrane 6 superfamily member 2(TM6SF2)gene E167K variant(rs58542926)was identified by exome-wide as-sociation study as a nonsynonymous single nucleotide poly-morphism associated with nonalcoholic fatty liver disease.The TM6SF2 E167K variant features a C-to-T substitution at nucleotide 499,encoding a glutamate with lysine change at codon 167(E167K).TM6SF2 is markedly expressed in the liver,small intestine and kidney,and has been proposed as an im-portant risk factor for diseases associated with lipid metabo-lism.Subsequently,multifunctional studies of the TM6SF2 E167K variant have been carried out in a spectrum of liver dis-eases,such as nonalcoholic fatty liver disease,nonalcoholic steatohepatitis,fibrosis,cirrhosis,and viral hepatitis.This re-view summarizes the research status of the TM6SF2 E167K variant in different liver diseases and specific populations,and discusses the potential mechanisms of the TM6SF2 E167K var-iant's role in the progression of various liver diseases.展开更多
Nutrient metabolism is regulated by several factors.Social determinants of health with or without genetics are the primary regulator of metabolism,and an unhealthy lifestyle affects all modulators and mediators,leadin...Nutrient metabolism is regulated by several factors.Social determinants of health with or without genetics are the primary regulator of metabolism,and an unhealthy lifestyle affects all modulators and mediators,leading to the adaptation and finally to the exhaustion of cellular functions.Hepatic steatosis is defined by presence of fat in more than 5%of hepatocytes.In hepatocytes,fat is stored as triglycerides in lipid droplet.Hepatic steatosis results from a combination of multiple intracellular processes.In a healthy individual nutrient metabolism is regulated at several steps.It ranges from the selection of nutrients in a grocery store to the last step of consumption of ATP as an energy or as a building block of a cell as structural component.Several hormones,peptides,and genes have been described that participate in nutrient metabolism.Several enzymes participate in each nutrient metabolism as described above from ingestion to generation of ATP.As of now several publications have revealed very intricate regulation of nutrient metabolism,where most of the regulatory factors are tied to each other bidirectionally,making it difficult to comprehend chronological sequence of events.Insulin hormone is the primary regulator of all nutrients’metabolism both in prandial and fasting states.Insulin exerts its effects directly and indirectly on enzymes involved in the three main cellular function processes;metabolic,inflammation and repair,and cell growth and regeneration.Final regulators that control the enzymatic functions through stimulation or suppression of a cell are nuclear receptors in especially farnesoid X receptor and peroxisome proliferator-activated receptor/RXR ligands,adiponectin,leptin,and adiponutrin.Insulin hormone has direct effect on these final modulators.Whereas blood glucose level,serum lipids,incretin hormones,bile acids in conjunction with microbiota are intermediary modulators which are controlled by lifestyle.The purpose of this review is to overview the key players in the pathogenesis of metabolic dysfunction-associated steatotic liver disease(MASLD)that help us understand the disease natural course,risk stratification,role of lifestyle and pharmacotherapy in each individual patient with MASLD to achieve personalized care and target the practice of precision medicine.PubMed and Google Scholar databases were used to identify publication related to metabolism of carbohydrate and fat in states of health and disease states;MASLD,cardiovascular disease and cancer.More than 1000 publications including original research and review papers were reviewed.展开更多
AIM: To investigate roles of genetic polymorphisms in non-alcoholic fatty liver disease (NAFLD) onset, severity, and outcome through systematic literature review.METHODS: The authors conducted both systematic and spec...AIM: To investigate roles of genetic polymorphisms in non-alcoholic fatty liver disease (NAFLD) onset, severity, and outcome through systematic literature review.METHODS: The authors conducted both systematic and specific searches of PubMed through December 2015 with special emphasis on more recent data (from 2012 onward) while still drawing from more historical data for background. We identified several specific genetic polymorphisms that have been most researched and, at this time, appear to have the greatest clinical significance on NAFLD and similar hepatic diseases. These were further investigated to assess their specific effects on disease onset and progression and the mechanisms by which these effects occur.RESULTS: We focus particularly on genetic polymorphisms of the following genes: PNPLA3, particularly the p. I148M variant, TM6SF2, particularly the p. E167K variant, and on variants in FTO, LIPA, IFNλ4, and iron metabolism, specifically focusing on HFE, and HMOX-1. We discuss the effect of these genetic variations and their resultant protein variants on the onset of fatty liver disease and its severity, including the effect on likelihood of progression to cirrhosis and hepatocellular carcinoma. While our principal focus is on NAFLD, we also discuss briefly effects of some of the variants on development and severity of other hepatic diseases, including hepatitis C and alcoholic liver disease. These results are briefly discussed in terms of clinical application and future potential for personalized medicine.CONCLUSION: Polymorphisms and genetic factors of several genes contribute to NAFLD and its end results. These genes hold keys to future improvements in diagnosis and management.展开更多
This review intends to uncover how information from large-scale genetic profiling(whole genome sequencing, and whole exome sequencing) of nonalcoholic fatty liver disease(NAFLD), as well as information from circulatin...This review intends to uncover how information from large-scale genetic profiling(whole genome sequencing, and whole exome sequencing) of nonalcoholic fatty liver disease(NAFLD), as well as information from circulating transcriptomics(cell-free mi RNAs) and metabolomics, contributes to the understanding of NAFLD pathogenesis. A further aim is to address the question of whether OMICs information is ready to be implemented in the clinics. The available evidence suggests that any new knowledge pertaining to molecular signatures associated with NAFLD and nonalcoholic steatohepatitis should be promptly translated into the clinical setting. Nevertheless, rigorous steps that must include validation and replication are mandatory before utilizing OMICs biomarkers in diagnostics to identify patients at risk of advanced disease, including liver cancer.展开更多
Classically, the non-alcoholic fatty liver disease(NAFLD) physiopathology and progression has been summarized in the two hits hypothesis. The first hit is represented by the action of hyperinsulinemia and insulin resi...Classically, the non-alcoholic fatty liver disease(NAFLD) physiopathology and progression has been summarized in the two hits hypothesis. The first hit is represented by the action of hyperinsulinemia and insulin resistance, accompanying obesity, that leads to liver steatosis increasing the absolute non esterified fatty acids uptake in the liver and the esterification to form triacylglycerol. The oxidative stress is involved in the second hit leading to the progression to nonalcoholic steatohepatitis(NASH) because of its harmful action on steatosic hepatocytes. However, at the present time, the two hits hypothesis needs to be updated because of the discover of genetic polymorphisms involved both in the liver fat accumulation and progression to NASH that make more intriguing understanding the NAFLD pathophysiological mechanisms. In this editorial, we want to underline the role of PNPLA3 I148 M, GPR120 R270 H and TM6SF2 E167 K in the pediatric NAFLD development because they add new pieces to the comprehension of the NAFLD pathophysiological puzzle. The PNPLA3 I148 M polymorphism encodes for an abnormal protein which predisposes to intrahepatic triglycerides accumulation both for a loss-of-function of its triglyceride hydrolase activity and for a gain-of-function of its lipogenic activity.Therefore, it is involved in the first hit, such as TM6SF2 E167 K polymorphisms that lead to intrahepatic fat accumulation through a reduced very low density lipoprotein secretion. On the other hand, the GPR120 R270 H variant, reducing the anti-inflammatory action of the GPR120 receptor expressed by Kuppfer cells, is involved in the second hit leading to the liver injury.展开更多
De novo non-alcoholic fatty liver disease(NAFLD) is a common late complication for long-term survivors after liver transplantation. Genomic studies confirmed that PNPLA3 I148 M and TM6SF2 E167 K polymorphisms affected...De novo non-alcoholic fatty liver disease(NAFLD) is a common late complication for long-term survivors after liver transplantation. Genomic studies confirmed that PNPLA3 I148 M and TM6SF2 E167 K polymorphisms affected NAFLD susceptibility in the general population. However,this association was not validated in survivors after liver transplantation(LT). We performed a crosssectional survey to investigate this relationship. A comprehensive survey,including anthropometric measurements,fasting venous blood sampling,ultrasound,and questionnaires was performed in the shortterm. The clinical indications and patient's steatosis status before LT were collected from inpatient medical records. Sixty-five long-term recipients with a survival exceeding 10 years were enrolled in the final analysis. De novo NAFLD was more frequent in PNPLA3 GG carriers(0.33 vs 0.10 for GG vs CC + CG carriers,P = 0.018),while the genetic impact on NAFLD susceptibility was insignificant when categorized by the TM6SF2 polymorphism(0.19 in CC vs 0.14 in CT + TT carriers,P = 0.883). Multi-covariate analysis revealed that PNPLA3 exerted a significant genetic effect on de novoNAFLD following a recessive model(GG vs CC + CG,OR = 14.2,95%CI:1.78-113,P = 0.012). Compared to recipients with only the PNPLA3 GG allele or obesity(defined as body mass index > 25 kg/m2),steatosis was highly prevalent(71.4%) in PNPLA3 GG carriers Table 1 Current status of long-term recipients surviving more than 10 years Univariate Multivariate NAFLD(n = 12)Control(n = 53)P value OR P value Age(yr) 56.5 ± 8.4 53.6 ± 10.1 0.356 1.04(0.92-1.18)0.528Gender(M/F) 10/2 47/6 0.611 1.40(0.14-14.2)0.427 Indication for LT Hepatitis/cirrhosis/ cancer/others1/8/2/17/35/9/20.889 Survival time(yr) 11.2 ± 0.9 11.5 ± 1.4 0.541 BMI(kg/m2) 25.1 ± 3.0 22.5 ± 2.6 0.003 1.47(1.03-2.08)0.032 TG(mmol/L) 1.6 ± 1.1 1.1 ± 0.6 0.038 1.34(0.38-4.71)0.652 HDL-C(mmol/L) 1.2(1.0-1.4) 1.3(1.0-1.7) 0.267 FBG(mmol/L) 7.6 ± 3.4 5.7 ± 1.9 0.013 1.49(0.93-2.37)0.095 Hypertension(Yes/no)3/9 21/32 0.343 SUA(μmol/L) 381.6 ± 75.6 342.6 ± 76.4 0.116 Met S(Yes/no) 4/8 9/44 0.201 ALT(U/L) 36.7 ± 7.0 38.8 ± 6.7 0.882 Alcohol intake(g/wk)11.6 ± 7.3 21.0 ± 8.2 0.766 Smoking(cigar/d) 4.2 ± 3.4 4.3 ± 1.2 0.969 Exercise(min/d) 18.5 ± 6.0 22.9 ± 2.9 0.513 Immunosuppression Tacrolimus/ cyclosporine/ MMF/sirolimus/ none11/1/0/0/036/12/1/2/20.575 PNPLA3(CC/CG/GG)1/3/8 16/21/16 0.018 14.2(1.78-113)0.012 TM6SF2(CC/CT/TT)11/1/0 47/5/1 0.883 2.68(0.25-28.5)0.413 Continuous variables with equal variance are presented as the mean ± SD; Continuous variables with unequal variance are presented as the median(interquartile range); Categorical variables are presented as the number of subjects. One-way ANOVA was used for the comparison between continuous variables with equal variance,Mann-Whitney U test was used for the comparison between continuous variables with unequal variance,chi-square test was used for the comparison between categorical variables in univariate analysis,and logistic regression analysis was used in the multivariate analysis. The effect of the PNPLA3 I148 M polymorphism was evaluated by a recessive genetic model(GG vs CG + CC); the effect of the TM6SF2 E167 K polymorphism was evaluated by a dominant genetic model(CC + CT vs TT) for decreased prevalence of TT carrier. ALT:Alanine aminotransferase; BMI:Body mass index; F:Female; FBG:Fasting blood glucose; HBs Ag:Hepatitis B surface antigen; HDL-C:Highdensity lipoprotein cholesterol; LT:Liver transplantation; M:Male; Met S:Metabolic syndrome; MMF:Mycophenolatemofetil; SUA:Serum uric acid; TG:Triglyceride. De novo NAFLD Controlwith obesity. In conclusion,PNPLA3 I148 M,but not TM6SF2 E167 K,affects de novo NAFLD occurrence with a prominent interaction with obesity. Weight control might be a meaningful method to reduce the genetic susceptibility to NAFLD exerted by PNPLA3 variants.展开更多
文摘AIM To evaluate the impact of the Glu167Lys(E167K) transmembrane 6 superfamily member 2(TM6SF2) variant on the biochemical and morphologic expression of liver lesions in human immunodeficiency virus(HIV)/hepatitis C virus(HCV) co-infected patients.METHODS The study comprised 167 consecutive patients with HIV/HCV coinfection and biopsy-proven chronic hepatitis. A pathologist graded liver fibrosis and necroinflammation using the Ishak scoring system, and steatosis using Kleiner's scoring system. Patients were genotyped for TM6SF2 E167K(rs58542926) by real-time Polymerase chain reaction. The 167 patients, 35 therapy-naive and 132 receiving ART, were prevalently males(73.6%), the median age was 40.7 years and the immunological condition good(median CD4+ cells/mm3 = 505.5).RESULTS The 17 patients with the TM6SF2 E167 K variant, compared with the 150 with TM6SF2-E/E, showed higher AST(P = 0.02) and alanine aminotransferase(P = 0.02) and higher fibrosis score(3.1 ± 2.0 vs 2.3 ± 1.5, P = 0.05). In a multivariate analysis, TM6SF2 E167 K was independently associated with severe fibrosis. The same analysis showed that HCV-genotype 3, present in 42.2% of patients was an independent predictor of severe steatosis. The association of TM6SF2 E167 K with severe steatosis, absent for the whole group of 167 patients, was re-evaluated separately for HCVgenotype 3 and non-3 patients: No factor was independently associated with severe steatosis in the HCV-genotype-3 subgroup, whereas an independent association was observed between severe steatosis and TM6SF2 E167 K in non-3 HCV genotypes. No association between the TM6SF2 E167 K variant and severe liver necroinflammation was observed.CONCLUSION In HIV/HCV coinfection the TM6SF2 E167 K variant is an independent predictor of severe fibrosis, but appears to be independently associated with severe steatosis only for patients with a non-3 HCV genotype.
基金Supported by National Natural Science Foundation of China,No.81670514 and No.81702337Scientific Research Project of Shanghai Municipal Health Commission,No.202040065Natural Science Foundation of Shanghai Scientific and Technological Project of Innovative Action,No.20ZR1411900.
文摘BACKGROUND The lack of effective pharmacotherapies for nonalcoholic fatty liver disease(NAFLD)is mainly attributed to insufficient research on its pathogenesis.The pathogenesis of TM6SF2-efficient NAFLD remains unclear,resulting in a lack of therapeutic strategies for TM6SF2-deficient patients.AIM To investigate the role of TM6SF2 in fatty acid metabolism in the context of fatty liver and propose possible therapeutic strategies for NAFLD caused by TM6SF2 deficiency.METHODS Liver samples collected from both NAFLD mouse models and human participants(80 cases)were used to evaluate the expression of TM6SF2 by using western blotting,immunohistochemistry,and quantitative polymerase chain reaction.RNA-seq data retrieved from the Gene Expression Omnibus database were used to confirm the over-expression of TM6SF2.Knockdown and overexpression of TM6SF2 were performed to clarify the mechanistic basis of hepatic lipid accumulation in NAFLD.MK-4074 administration was used as a therapeutic intervention to evaluate its effect on NAFLD caused by TM6SF2 deficiency.RESULTS Hepatic TM6SF2 levels were elevated in patients with NAFLD and NAFLD mouse models.TM6SF2 overexpression can reduce hepatic lipid accumulation,suggesting a protective role for TM6SF2 in a high-fat diet(HFD).Downregulation of TM6SF2,simulating the TM6SF2 E167K mutation condition,increases intracellular lipid deposition due to dysregulated fatty acid metabolism and is characterized by enhanced fatty acid uptake and synthesis,accompanied by impaired fatty acid oxidation.Owing to the potential effect of TM6SF2 deficiency on lipid metabolism,the application of an acetyl-CoA carboxylase inhibitor(MK-4074)could reverse the NAFLD phenotypes caused by TM6SF2 deficiency.CONCLUSION TM6SF2 plays a protective role in the HFD condition;its deficiency enhanced hepatic lipid accumulation through dysregulated fatty acid metabolism,and MK-4074 treatment could alleviate the NAFLD phenotypes caused by TM6SF2 deficiency.
基金This study was supported by Qingdao Livelihood,Science and Technology Project,China(14-2-3-17-nsh)Qingdao Key Health Discipline Development Fund.In addition,this project was supported by the Medjaden Academy & Research Foundation for Young Scientists(Grant MJA20150831)
文摘Nonalcoholic fatty liver disease(NAFLD)is one of the most common causes of liver dysfunction worldwide,and its prevalence is highly associated with genetic susceptibility.The transmembrane 6 superfamily member 2(TM6SF2)E167K variant represents a general genetic determinant of hepatic triglyceride content and lobular inflammation,and its presence appears to be directly involved in the pathogenesis and development of NAFLD.Although this variant appears to be a novel powerful modifier in the development of NAFLD,whether it is associated with an increased risk of NAFLD-refated liver fibrosis and hepatocellular carcinoma(HCC)remains to be determined.The aim of this review is to describe the functions of the TM6SF2 E167K variant and its association with NAFLD,with particular emphasis on the underlying mechanisms of its role in the development and progression of NAFLD.Additionally,the links between the TM6SF2 E167K variant and NAFLD-related liver fibrosis and HCC will be discussed.
基金supported by grants from the National Natural Science Foundation of China(No.31770837)the Key Research Project of Shandong Province(No.2016GSF201217)the Qingdao,Shinan District Science and Technology Development Project Fund(No.2016-3-016-YY)
文摘Background and Aims:Accumulated evidence has shown that chronic liver inflammation is one of the main risks of hepatocellular carcinoma(HCC),and E167K variant of the transmembrane 6 superfamily member 2(TM6SF2)plays an important role in the progression of chronic liver diseases and HCC.The aim of this study was to explore effects of the TM6SF2 E167K variant on expression of the inflammatory cytokines TNF-cα,IL-2,IL-6 and IL-8 in the HCC cell line HEPA 1-6.Methods:HEPA 1-6 cells were infected with lentivirus containing either the TM6SF2 E167K variant or TM6SF2 wildtype,or control plasmids.Quantitative real-time polymerase chain reaction(qRT-PCR)and western blotting were conducted to analyze the expression of the inflammatory cytokines TNF-α,IL-2,IL-6 and IL-8.A t-test was used for statistical analysis.Results:Compared with the control group and TM6SF2 overexpression group,the relative expression of IL-2 and IL-6 mRNAs were significantly elevated in the TM6SF2 E167K overexpression group(p<0.05).The relative mRNA expression of IL-8 in theTM6SF2 and TM6SF2 E167K overexpression groups were increased compared to the control group(p<0.05).No obvious differences were observed for the expression of TNF-αin each group.The expression of TNF-α,IL-2,IL-6 and IL-8 that was tested by western blotting showed the same trends as the qRT-PCR results.Conclusions:In conclusion,the E167K variant of theTM6SF2 gene could promote the expression of inflammatory cytokines IL-2 and IL-6 in HEPA 1-6 cells,suggesting that the TM6SF2 E167K variant may accelerate the progression of HCC.
基金supported by grants from the National Natural Science Foundation of China(31770837)the Key Research Project of Shandong Province(2016GSF201217)the Qingdao,Shinan District Science and Technology Development Project Fund(2016-3-016-YY)
文摘The transmembrane 6 superfamily member 2(TM6SF2)gene E167K variant(rs58542926)was identified by exome-wide as-sociation study as a nonsynonymous single nucleotide poly-morphism associated with nonalcoholic fatty liver disease.The TM6SF2 E167K variant features a C-to-T substitution at nucleotide 499,encoding a glutamate with lysine change at codon 167(E167K).TM6SF2 is markedly expressed in the liver,small intestine and kidney,and has been proposed as an im-portant risk factor for diseases associated with lipid metabo-lism.Subsequently,multifunctional studies of the TM6SF2 E167K variant have been carried out in a spectrum of liver dis-eases,such as nonalcoholic fatty liver disease,nonalcoholic steatohepatitis,fibrosis,cirrhosis,and viral hepatitis.This re-view summarizes the research status of the TM6SF2 E167K variant in different liver diseases and specific populations,and discusses the potential mechanisms of the TM6SF2 E167K var-iant's role in the progression of various liver diseases.
文摘Nutrient metabolism is regulated by several factors.Social determinants of health with or without genetics are the primary regulator of metabolism,and an unhealthy lifestyle affects all modulators and mediators,leading to the adaptation and finally to the exhaustion of cellular functions.Hepatic steatosis is defined by presence of fat in more than 5%of hepatocytes.In hepatocytes,fat is stored as triglycerides in lipid droplet.Hepatic steatosis results from a combination of multiple intracellular processes.In a healthy individual nutrient metabolism is regulated at several steps.It ranges from the selection of nutrients in a grocery store to the last step of consumption of ATP as an energy or as a building block of a cell as structural component.Several hormones,peptides,and genes have been described that participate in nutrient metabolism.Several enzymes participate in each nutrient metabolism as described above from ingestion to generation of ATP.As of now several publications have revealed very intricate regulation of nutrient metabolism,where most of the regulatory factors are tied to each other bidirectionally,making it difficult to comprehend chronological sequence of events.Insulin hormone is the primary regulator of all nutrients’metabolism both in prandial and fasting states.Insulin exerts its effects directly and indirectly on enzymes involved in the three main cellular function processes;metabolic,inflammation and repair,and cell growth and regeneration.Final regulators that control the enzymatic functions through stimulation or suppression of a cell are nuclear receptors in especially farnesoid X receptor and peroxisome proliferator-activated receptor/RXR ligands,adiponectin,leptin,and adiponutrin.Insulin hormone has direct effect on these final modulators.Whereas blood glucose level,serum lipids,incretin hormones,bile acids in conjunction with microbiota are intermediary modulators which are controlled by lifestyle.The purpose of this review is to overview the key players in the pathogenesis of metabolic dysfunction-associated steatotic liver disease(MASLD)that help us understand the disease natural course,risk stratification,role of lifestyle and pharmacotherapy in each individual patient with MASLD to achieve personalized care and target the practice of precision medicine.PubMed and Google Scholar databases were used to identify publication related to metabolism of carbohydrate and fat in states of health and disease states;MASLD,cardiovascular disease and cancer.More than 1000 publications including original research and review papers were reviewed.
文摘AIM: To investigate roles of genetic polymorphisms in non-alcoholic fatty liver disease (NAFLD) onset, severity, and outcome through systematic literature review.METHODS: The authors conducted both systematic and specific searches of PubMed through December 2015 with special emphasis on more recent data (from 2012 onward) while still drawing from more historical data for background. We identified several specific genetic polymorphisms that have been most researched and, at this time, appear to have the greatest clinical significance on NAFLD and similar hepatic diseases. These were further investigated to assess their specific effects on disease onset and progression and the mechanisms by which these effects occur.RESULTS: We focus particularly on genetic polymorphisms of the following genes: PNPLA3, particularly the p. I148M variant, TM6SF2, particularly the p. E167K variant, and on variants in FTO, LIPA, IFNλ4, and iron metabolism, specifically focusing on HFE, and HMOX-1. We discuss the effect of these genetic variations and their resultant protein variants on the onset of fatty liver disease and its severity, including the effect on likelihood of progression to cirrhosis and hepatocellular carcinoma. While our principal focus is on NAFLD, we also discuss briefly effects of some of the variants on development and severity of other hepatic diseases, including hepatitis C and alcoholic liver disease. These results are briefly discussed in terms of clinical application and future potential for personalized medicine.CONCLUSION: Polymorphisms and genetic factors of several genes contribute to NAFLD and its end results. These genes hold keys to future improvements in diagnosis and management.
基金Supported by Agencia Nacional de Promoción Científicay Tecnológica,No.PICT 2014-0432,No.PICT 2014-1816 and No.PICT 2015-0551
文摘This review intends to uncover how information from large-scale genetic profiling(whole genome sequencing, and whole exome sequencing) of nonalcoholic fatty liver disease(NAFLD), as well as information from circulating transcriptomics(cell-free mi RNAs) and metabolomics, contributes to the understanding of NAFLD pathogenesis. A further aim is to address the question of whether OMICs information is ready to be implemented in the clinics. The available evidence suggests that any new knowledge pertaining to molecular signatures associated with NAFLD and nonalcoholic steatohepatitis should be promptly translated into the clinical setting. Nevertheless, rigorous steps that must include validation and replication are mandatory before utilizing OMICs biomarkers in diagnostics to identify patients at risk of advanced disease, including liver cancer.
文摘Classically, the non-alcoholic fatty liver disease(NAFLD) physiopathology and progression has been summarized in the two hits hypothesis. The first hit is represented by the action of hyperinsulinemia and insulin resistance, accompanying obesity, that leads to liver steatosis increasing the absolute non esterified fatty acids uptake in the liver and the esterification to form triacylglycerol. The oxidative stress is involved in the second hit leading to the progression to nonalcoholic steatohepatitis(NASH) because of its harmful action on steatosic hepatocytes. However, at the present time, the two hits hypothesis needs to be updated because of the discover of genetic polymorphisms involved both in the liver fat accumulation and progression to NASH that make more intriguing understanding the NAFLD pathophysiological mechanisms. In this editorial, we want to underline the role of PNPLA3 I148 M, GPR120 R270 H and TM6SF2 E167 K in the pediatric NAFLD development because they add new pieces to the comprehension of the NAFLD pathophysiological puzzle. The PNPLA3 I148 M polymorphism encodes for an abnormal protein which predisposes to intrahepatic triglycerides accumulation both for a loss-of-function of its triglyceride hydrolase activity and for a gain-of-function of its lipogenic activity.Therefore, it is involved in the first hit, such as TM6SF2 E167 K polymorphisms that lead to intrahepatic fat accumulation through a reduced very low density lipoprotein secretion. On the other hand, the GPR120 R270 H variant, reducing the anti-inflammatory action of the GPR120 receptor expressed by Kuppfer cells, is involved in the second hit leading to the liver injury.
基金Supported by National S and T Major Project,No.2012ZX 10002017Foundation for Innovative Research Groups of the National Natural Science Foundation of China,Grant No.81421062China Postdoctoral Science Foundation Project,No.2015M570518
文摘De novo non-alcoholic fatty liver disease(NAFLD) is a common late complication for long-term survivors after liver transplantation. Genomic studies confirmed that PNPLA3 I148 M and TM6SF2 E167 K polymorphisms affected NAFLD susceptibility in the general population. However,this association was not validated in survivors after liver transplantation(LT). We performed a crosssectional survey to investigate this relationship. A comprehensive survey,including anthropometric measurements,fasting venous blood sampling,ultrasound,and questionnaires was performed in the shortterm. The clinical indications and patient's steatosis status before LT were collected from inpatient medical records. Sixty-five long-term recipients with a survival exceeding 10 years were enrolled in the final analysis. De novo NAFLD was more frequent in PNPLA3 GG carriers(0.33 vs 0.10 for GG vs CC + CG carriers,P = 0.018),while the genetic impact on NAFLD susceptibility was insignificant when categorized by the TM6SF2 polymorphism(0.19 in CC vs 0.14 in CT + TT carriers,P = 0.883). Multi-covariate analysis revealed that PNPLA3 exerted a significant genetic effect on de novoNAFLD following a recessive model(GG vs CC + CG,OR = 14.2,95%CI:1.78-113,P = 0.012). Compared to recipients with only the PNPLA3 GG allele or obesity(defined as body mass index > 25 kg/m2),steatosis was highly prevalent(71.4%) in PNPLA3 GG carriers Table 1 Current status of long-term recipients surviving more than 10 years Univariate Multivariate NAFLD(n = 12)Control(n = 53)P value OR P value Age(yr) 56.5 ± 8.4 53.6 ± 10.1 0.356 1.04(0.92-1.18)0.528Gender(M/F) 10/2 47/6 0.611 1.40(0.14-14.2)0.427 Indication for LT Hepatitis/cirrhosis/ cancer/others1/8/2/17/35/9/20.889 Survival time(yr) 11.2 ± 0.9 11.5 ± 1.4 0.541 BMI(kg/m2) 25.1 ± 3.0 22.5 ± 2.6 0.003 1.47(1.03-2.08)0.032 TG(mmol/L) 1.6 ± 1.1 1.1 ± 0.6 0.038 1.34(0.38-4.71)0.652 HDL-C(mmol/L) 1.2(1.0-1.4) 1.3(1.0-1.7) 0.267 FBG(mmol/L) 7.6 ± 3.4 5.7 ± 1.9 0.013 1.49(0.93-2.37)0.095 Hypertension(Yes/no)3/9 21/32 0.343 SUA(μmol/L) 381.6 ± 75.6 342.6 ± 76.4 0.116 Met S(Yes/no) 4/8 9/44 0.201 ALT(U/L) 36.7 ± 7.0 38.8 ± 6.7 0.882 Alcohol intake(g/wk)11.6 ± 7.3 21.0 ± 8.2 0.766 Smoking(cigar/d) 4.2 ± 3.4 4.3 ± 1.2 0.969 Exercise(min/d) 18.5 ± 6.0 22.9 ± 2.9 0.513 Immunosuppression Tacrolimus/ cyclosporine/ MMF/sirolimus/ none11/1/0/0/036/12/1/2/20.575 PNPLA3(CC/CG/GG)1/3/8 16/21/16 0.018 14.2(1.78-113)0.012 TM6SF2(CC/CT/TT)11/1/0 47/5/1 0.883 2.68(0.25-28.5)0.413 Continuous variables with equal variance are presented as the mean ± SD; Continuous variables with unequal variance are presented as the median(interquartile range); Categorical variables are presented as the number of subjects. One-way ANOVA was used for the comparison between continuous variables with equal variance,Mann-Whitney U test was used for the comparison between continuous variables with unequal variance,chi-square test was used for the comparison between categorical variables in univariate analysis,and logistic regression analysis was used in the multivariate analysis. The effect of the PNPLA3 I148 M polymorphism was evaluated by a recessive genetic model(GG vs CG + CC); the effect of the TM6SF2 E167 K polymorphism was evaluated by a dominant genetic model(CC + CT vs TT) for decreased prevalence of TT carrier. ALT:Alanine aminotransferase; BMI:Body mass index; F:Female; FBG:Fasting blood glucose; HBs Ag:Hepatitis B surface antigen; HDL-C:Highdensity lipoprotein cholesterol; LT:Liver transplantation; M:Male; Met S:Metabolic syndrome; MMF:Mycophenolatemofetil; SUA:Serum uric acid; TG:Triglyceride. De novo NAFLD Controlwith obesity. In conclusion,PNPLA3 I148 M,but not TM6SF2 E167 K,affects de novo NAFLD occurrence with a prominent interaction with obesity. Weight control might be a meaningful method to reduce the genetic susceptibility to NAFLD exerted by PNPLA3 variants.
