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 TIF1γ-suppression, leading to liver fibrosis. Here, we examined the mechanism how reduction of TIF1γ in HSCs induces damage on hepatocytes and liver fibrosis. Method: Lrat:Cas9-ERT2:sgTif1γ mice were treated Tamoxifen (TMX) or wild-type mice were treated Thioacetamide (TAA). HSCs were isolated from mice liver and analyzed role of Tif1γ. HepG2 were treated retinol with/without siRNA for Stimulated by retinoic acid 6 (STRA6) or Retinoic acid receptor(RAR)-antagonist, and LX2 were treated siTIF1γ and/or siSTRA6. TAA treated mice were used for evaluation of siSTRA6 effect in liver fibrosis. Results: When we blocked the Tif1γ in HSCs using Lrat:Cas9-ERT2:sgTif1γ 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, TIF1γ-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 TIF1γ-reduction is taken up by hepatocytes via STRA6, leading to fat-deposition and damage, and liver fibrosis. [Figure not available: see fulltext.]