In vitro analysis of hepatic stellate cell activation influenced by transmembrane 6 superfamily 2 polymorphism.

ABSTRACT: Non?alcoholic steatohepatitis (NASH) may progress via liver fibrosis along with hepatic stellate cell (HSC) activation. A single nucleotide polymorphism (SNP; rs58542926) located in transmembrane 6 superfamily 2 (TM6SF2) has been reported to be significantly associated with fibrosis in patients with NASH, but the precise mechanism is still unknown. The present study aimed to explore the role of TM6SF2 in HSC activation in vitro. Plasmids producing TM6SF2 wild-type (WT) and mutant type (MT) containing E167K amino acid substitution were constructed, and the activation of LX?2 cells was analyzed by overexpressing or knocking down TM6SF2 under transforming growth factor ?1 (TGF?) treatment. Intracellular ??smooth muscle actin (?SMA) expression in LX?2 cells was significantly repressed by TM6SF2?WT overexpression and increased by TM6SF2 knockdown. Following treatment with TGF?, ?SMA expression was restored in TM6SF2?WT overexpressed LX?2 cells and was enhanced in TM6SF2 knocked?down LX?2 cells. Comparing ?SMA expression under TM6SF2?WT or ?MT overexpression, expression of ?SMA in TM6SF2?MT overexpressed cells was higher than that in TM6SF2?WT cells and was further enhanced by TGF? treatment. The present study demonstrated that intracellular ?SMA expression in HCS was negatively regulated by TM6SF2 while the E167K substitution released this negative regulation and led to enhanced HSC activation by TGF?. These results suggest that the SNP in TM6SF2 may relate to sensitivity of HSC activation.

SUBMITTER: Liu S 

PROVIDER: S-EPMC7673330 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature