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

Cited 7 time in Web of Science Cited 7 time in Scopus
Authors

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

Issue Date
2021-01-06
Publisher
BMC
Citation
Cell & Bioscience. 2021 Jan 06;11(1):3
Keywords
RetinolHepatocytesStimulated by retinoic acid 6 (STRA6)LipogenesisLiver fbrosis
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.
ISSN
2045-3701
Language
English
URI
https://hdl.handle.net/10371/173589
DOI
https://doi.org/10.1186/s13578-020-00509-w
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