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

Abstract

BackgroundHepatic stellate cells (HSCs) are activated in response to liver injury with TIF1 gamma -suppression, leading to liver fibrosis. Here, we examined the mechanism how reduction of TIF1 gamma in HSCs induces damage on hepatocytes and liver fibrosis.MethodLrat:Cas9-ERT2:sgTif1 gamma mice were treated Tamoxifen (TMX) or wild-type mice were treated Thioacetamide (TAA). HSCs were isolated from mice liver and analyzed role of Tif1 gamma. 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 gamma and/or siSTRA6. TAA treated mice were used for evaluation of siSTRA6 effect in liver fibrosis.ResultsWhen we blocked the Tif1 gamma in HSCs using Lrat:Cas9-ERT2:sgTif1 gamma 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 gamma -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.ConclusionsRetinol from HSCs via STRA6 in response to injury with TIF1 gamma -reduction is taken up by hepatocytes via STRA6, leading to fat-deposition and damage, and liver fibrosis.