Retinol from hepatic stellate cells via STRA6 induces lipogenesis on hepatocytes during fibrosis.

ABSTRACT:

Background

Hepatic stellate cells (HSCs) are activated in response to liver injury with TIF1?-suppression, leading to liver fibrosis. Here, we examined the mechanism how reduction of TIF1? in HSCs induces damage on hepatocytes and liver fibrosis.

Method

Lrat:Cas9-ERT2:sgTif1? mice were treated Tamoxifen (TMX) or wild-type mice were treated Thioacetamide (TAA). HSCs were isolated from mice liver and analyzed role of Tif1?. HepG2 were treated retinol with/without siRNA for Stimulated by retinoic acid 6 (STRA6) or Retinoic acid receptor(RAR)-antagonist, and LX2 were treated siTIF1? and/or siSTRA6. TAA treated mice were used for evaluation of siSTRA6 effect in liver fibrosis.

Results

When we blocked the Tif1? in HSCs using Lrat:Cas9-ERT2:sgTif1? mice, retinol is distributed into hepatocytes. Retinol influx was confirmed using HepG2, and the increased intracellular retinol led to the upregulation of lipogenesis-related-genes and triglyceride. This effect was inhibited by a RAR-antagonist or knock-down of STRA6. In the LX2, TIF1?-suppression resulted in upregulation of STRA6 and retinol release, which was inhibited by STRA6 knock-down. The role of STRA6-mediated retinol transfer from HSCs to hepatocytes in liver fibrosis was demonstrated by in vivo experiments where blocking of STRA6 reduced fibrosis.

Conclusions

Retinol from HSCs via STRA6 in response to injury with TIF1?-reduction is taken up by hepatocytes via STRA6, leading to fat-deposition and damage, and liver fibrosis.

SUBMITTER: Hwang I 

PROVIDER: S-EPMC7789180 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature