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

Injoo Hwang,Dodam Moon,Eun Ju Lee,Hyomin Park,Hyo-Soo Kim

doi:10.1186/s13578-020-00509-w

Injoo Hwang, Dodam Moon + Show 3 more

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https://doi.org/10.1186/s13578-020-00509-w

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Abstract

BackgroundHepatic 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.MethodLrat: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.ResultsWhen 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.ConclusionsRetinol 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.

Highlights

Hepatic stellate cells (HSCs) are activated in response to liver injury with transcriptional intermediary factor 1γ (TIF1γ)-suppression, leading to liver fibrosis
When we blocked the Tif1γ in HSCs using Lrat-specific Tif1γ knockout transgenic mice (Lrat):Cas9-ERT2:sgTif1γ mice, retinol is distributed into hepatocytes
Retinol released from HSCs promotes the accumulation of triglyceride in hepatocytes To know the association between liver fibrosis driven by HSCs and intracellular amount of retinol in HSCs, we isolated primary HSCs from Lrat-specific Tif1γ knockout transgenic mice (Lrat:Cas9-ERT2: sgTif1γ) [16] and cultured them for 3 days in the presence of 10 nM tamoxifen (TMX) to reduce TIF1γ levels, a negative regulator against fibrosis

Summary

Introduction

Hepatic stellate cells (HSCs) are activated in response to liver injury with TIF1γ-suppression, leading to liver fibrosis. We examined the mechanism how reduction of TIF1γ in HSCs induces damage on hepatocytes and liver fibrosis. To overcome or prevent liver cirrhosis, it is essential to elucidate the molecular mechanisms by which fibrosis begins and progresses. Hepatic stellate cells (HSCs) are a major source of myofibroblasts in the fibrotic liver. The activation of HSCs by fibrosis-related signals, such as transforming growth factor β (TGFβ), induces their trans-differentiation into myofibroblasts, which exacerbate fibrosis by promoting extracellular matrix deposition [3,4,5,6]. Retinol (vitamin A), a common component of a wide variety of nutritional supplements, is a signaling substance that plays an essential role in the body. Retinol is stored almost in HSCs [7], but

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