Hepatocyte-specific TM6SF2 knockout aggravates hepatic steatosis in mice with nonalcoholic fatty liver disease / 临床肝胆病杂志

Objective To establish a mouse model of hepatocyte-specific TM6SF2 knockout, and to investigate the role of TM6SF2 in the development of nonalcoholic fatty liver disease (NAFLD). Methods The CRISPR/Cas9 technique and the Cre/LoxP strategy were used to establish a stable mouse model of hepatocyte-specific TM6SF2 knockout. The mice with hepatocyte-specific TM6SF2 knockout and the control mice were given a normal diet or a high-fat diet (HFD) for 16 weeks, and related indices were measured, including general status (body weight and liver weight), glucose metabolic indices (fasting blood glucose and insulin), and lipid metabolism (plasma triglyceride, cholesterol, and liver triglyceride). The t -test was used for comparison of normally distributed continuous data between two groups. Results Under the condition of HFD, compared with the control mice, the mice with hepatocyte-specific TM6SF2 knockout had significantly higher liver weight (2.235±0.175 g vs 1.258±0.106 g, t =4.789, P 0.05). Under the condition of HFD, there were no significant differences in the levels of plasma triglyceride and cholesterol between the mice with hepatocyte-specific TM6SF2 knockout and the control group ( P > 0.05), while the mice with hepatocyte-specific TM6SF2 knockout had a significant increase in the level of liver triglyceride compared with the control mice (23.969±0.978 mg/g vs 18.229±1.633 mg/g, t =3.015, P =0.024). Conclusion Hepatocyte-specific knockout of TM6SF2 can aggravate liver lipid accumulation and liver injury in mice with NAFLD.

Association between TM6SF2 rs58542926 polymorphism and non-alcoholic fatty liver disease in Qingdao Han population and molecular mechanism / 解放军医学杂志

Objective To investigate the association between the TM6SF2 rs58542926 polymorphism and non-alcoholic fatty liver disease (NAFLD) in Qingdao Han Population, and the molecular mechanism of TM6SF2 167 locus polymorphism affecting lipid metabolism. Methods We genotyped a cohort of NAFLD patients (NAFLD group) treated in Qingdao Municipal Hospital from Octorber 2016 to November 2017 and 451 healthy controls (control group) matched for age and sex by polymerase chain reaction and direct sequencing. Distribution of genotypes and allele frequencies of TM6SF2 rs58542926 and the relative risk of NAFLD were assessed. In addition, we concentrated the lentivirus of TM6SF2-mutant type and TM6SF2-wild type and transfected into Hepa1-6 cells. The concentration of lipid indicators and the expressions of SREBP-1c mRNA and protein were determined. Results There were significant differences in the genotype and allele frequencies of TM6SF2 rs58542926 polymorphism between the NAFLD and control group (P<0.001). Carriers of T allele had significantly increased susceptibility to NAFLD (OR=2.327, 95%CI: 1.542-3.513, P<0.001). Total cholesterol (TC) and triglyceride (TG) contents of the TM6SF2-mutant type group were both increased to high levels when compared with the TM6SF2-wild type group (P<0.001). Furthermore, the expression levels of sterol regulatory element-binding transcription factor 1c (SREBP-1c) mRNAs and protein of the TM6SF2-mutant type group were significantly increased when compared with either of the TM6SF2-wild type group (P<0.001). Conclusions The TM6SF2 rs58542926 polymorphism is associated with risk of NAFLD in Qingdao Han Population. Furthermore, the mutant T allele at TM6SF2 167 locus may regulate the hepatic lipid metabolism through increasing the expression of SREBP-1c.

Genetic predisposition in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease whose prevalence has reached global epidemic proportions. Although the disease is relatively benign in the early stages, when severe clinical forms, including nonalcoholic steatohepatitis (NASH), cirrhosis and even hepatocellular carcinoma, occur, they result in worsening the long-term prognosis. A growing body of evidence indicates that NAFLD develops from a complex process in which many factors, including genetic susceptibility and environmental insults, are involved. In this review, we focused on the genetic component of NAFLD, with special emphasis on the role of genetics in the disease pathogenesis and natural history. Insights into the topic of the genetic susceptibility in lean individuals with NAFLD and the potential use of genetic tests in identifying individuals at risk are also discussed.