Dataset Information

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

ACCESS DATA

Publications

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

Hwang Injoo I Lee Eun Ju EJ Park Hyomin H Moon Dodam D Kim Hyo-Soo HS

Cell & bioscience 20210106 1

<h4>Background</h4>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.<h4>Method</h4>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 Stimulate ...[more]

PMID: 33407858

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Project description:The fibrogenic wound-healing response in liver increases stiffness. Stiffness mechanotransduction, in turn, amplifies fibrogenesis. Here, we aimed to understand the distribution of stiffness in fibrotic liver, how it impacts hepatic stellate cell (HSC) heterogeneity, and identify mechanisms by which stiffness amplifies fibrogenic responses. Magnetic resonance elastography and atomic force microscopy demonstrated a heterogeneous distribution of liver stiffness at macroscopic and microscopic levels, respectively, in a carbon tetrachloride (CCl4) mouse model of liver fibrosis as compared with controls. High stiffness was mainly attributed to extracellular matrix dense areas. To identify a stiffness-sensitive HSC subpopulation, we performed single-cell RNA sequencing (scRNA-seq) on primary HSCs derived from healthy versus CCl4-treated mice. A subcluster of HSCs was matrix-associated with the most upregulated pathway in this subpopulation being focal adhesion signaling, including a specific protein termed four and a half LIM domains protein 2 (FHL2). In vitro, FHL2 expression was increased in primary human HSCs cultured on stiff matrix as compared with HSCs on soft matrix. Moreover, FHL2 knockdown inhibited fibronectin and collagen 1 expression, whereas its overexpression promoted matrix production. In summary, we demonstrate stiffness heterogeneity at the whole organ, lobular, and cellular level, which drives an amplification loop of fibrogenesis through specific focal adhesion molecular pathways.NEW & NOTEWORTHY The fibrogenic wound-healing response in liver increases stiffness. Here, macro and microheterogeneity of liver stiffness correlate with HSC heterogeneity in a hepatic fibrosis mouse model. Fibrogenic HSCs localized in stiff collagen-high areas upregulate the expression of focal adhesion molecule FHL2, which, in turn, promotes extracellular matrix protein expression. These results demonstrate that stiffness heterogeneity at the whole organ, lobular, and cellular level drives an amplification loop of fibrogenesis through specific focal adhesion molecular pathways.

Dataset Information

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

Background

Method

Results

Conclusions

Publications

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

Similar Datasets

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