The adiponectin-PPARγ axis in hepatic stellate cells regulates liver fibrosis

Shangang Zhao; Qingzhang Zhu; Wang Hsin Lee; Jan Bernd Funcke; Zhuzhen Zhang; May Yun Wang; Qian Lin; Bianca Field; Xue Nan Sun; Guannan Li; Mbolle Ekane; Toshiharu Onodera; Na Li; Yi Zhu; Christine M. Kusminski; Terry D. Hinds; Philipp E. Scherer

doi:10.1016/j.celrep.2024.115165

The adiponectin-PPARγ axis in hepatic stellate cells regulates liver fibrosis

Shangang Zhao, Qingzhang Zhu, Wang Hsin Lee, Jan Bernd Funcke, Zhuzhen Zhang, May Yun Wang, Qian Lin, Bianca Field, Xue Nan Sun, Guannan Li, Mbolle Ekane, Toshiharu Onodera, Na Li, Yi Zhu, Christine M. Kusminski, Terry D. Hinds, Philipp E. Scherer

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

Hepatic stellate cells (HSCs) are key drivers of local fibrosis. Adiponectin, conventionally thought of as an adipokine, is also expressed in quiescent HSCs. However, the impact of its local expression on the progression of liver fibrosis remains unclear. We recently generated a transgenic mouse line (Lrat-rtTA) that expresses the doxycycline-responsive transcriptional activator rtTA under the control of the HSC-specific lecithin retinol acyltransferase (Lrat) promoter, which enables us to specifically and inducibly overexpress or eliminate genes in these cells. The inducible elimination of HSCs protects mice from methionine/choline-deficient (MCD) diet-induced liver fibrosis, confirming their causal involvement in fibrosis development. We generated HSC-specific adiponectin overexpression and null models that demonstrate that HSC-specific adiponectin overexpression dramatically reduces liver fibrosis, whereas HSC-specific adiponectin elimination accelerates fibrosis progression. We identify a local adiponectin-peroxisome proliferator-activated receptor gamma (PPARγ) axis in HSCs that exerts a marked influence on the progression of local fibrosis, independent of circulating adiponectin derived from adipocytes.

Original language	English
Article number	115165
Journal	Cell Reports
Volume	44
Issue number	1
DOIs	https://doi.org/10.1016/j.celrep.2024.115165
State	Published - Jan 28 2025

Bibliographical note

Publisher Copyright:
© 2024 The Authors

Funding

This work was supported by the US National Institutes of Health grants R01-DK55758 , R01-DK099110 , RC2-DK118620 , R01-DK127274 , R01-DK131537 , and P01-AG051459 . It was also supported in part by a research grant from the Investigators Studies Research Program of Merck Sharp & Dohme Corp (to P.E.S.). The opinions expressed in this paper are those of the investigators and do not necessarily represent those of Merck Sharp & Dohme Corp. S.Z. was supported by the US National Institutes of Health grants R00-AG068239 , R01-DK138035 , and R01-AG084646 , Hevolution Fund (HF-GRO-23-1199262-27), and a Voelcker Fund Young Investigator grant. Y.Z. was supported by the US National Institutes of Health grants R01-DK136619 and R01-DK136532 . Q.Z. was supported by a Career Development Award from the American Heart Association (AHA 855170). We would like to thank Karen Kazandjian for help with the graphical abstract.

Funders	Funder number
National Institutes of Health (NIH)	RC2-DK118620, R01-DK55758, P01-AG051459, R01-DK127274, R01-DK099110, R01-DK131537
National Institutes of Health (NIH)
American the American Heart Association	855170
American the American Heart Association
Merck Sharp and Dohme United Kingdom	R00-AG068239, R01-DK138035, R01-DK136532, R01-AG084646, R01-DK136619, HF-GRO-23-1199262-27
Merck Sharp and Dohme United Kingdom

Keywords

CP: Metabolism
PPARγ
adiponectin
liver fibrosis
obesity

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2024.115165

Cite this

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title = "The adiponectin-PPARγ axis in hepatic stellate cells regulates liver fibrosis",

abstract = "Hepatic stellate cells (HSCs) are key drivers of local fibrosis. Adiponectin, conventionally thought of as an adipokine, is also expressed in quiescent HSCs. However, the impact of its local expression on the progression of liver fibrosis remains unclear. We recently generated a transgenic mouse line (Lrat-rtTA) that expresses the doxycycline-responsive transcriptional activator rtTA under the control of the HSC-specific lecithin retinol acyltransferase (Lrat) promoter, which enables us to specifically and inducibly overexpress or eliminate genes in these cells. The inducible elimination of HSCs protects mice from methionine/choline-deficient (MCD) diet-induced liver fibrosis, confirming their causal involvement in fibrosis development. We generated HSC-specific adiponectin overexpression and null models that demonstrate that HSC-specific adiponectin overexpression dramatically reduces liver fibrosis, whereas HSC-specific adiponectin elimination accelerates fibrosis progression. We identify a local adiponectin-peroxisome proliferator-activated receptor gamma (PPARγ) axis in HSCs that exerts a marked influence on the progression of local fibrosis, independent of circulating adiponectin derived from adipocytes.",

keywords = "CP: Metabolism, PPARγ, adiponectin, liver fibrosis, obesity",

author = "Shangang Zhao and Qingzhang Zhu and Lee, \{Wang Hsin\} and Funcke, \{Jan Bernd\} and Zhuzhen Zhang and Wang, \{May Yun\} and Qian Lin and Bianca Field and Sun, \{Xue Nan\} and Guannan Li and Mbolle Ekane and Toshiharu Onodera and Na Li and Yi Zhu and Kusminski, \{Christine M.\} and Hinds, \{Terry D.\} and Scherer, \{Philipp E.\}",

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day = "28",

doi = "10.1016/j.celrep.2024.115165",

language = "English",

volume = "44",

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AU - Zhao, Shangang

AU - Zhu, Qingzhang

AU - Lee, Wang Hsin

AU - Funcke, Jan Bernd

AU - Zhang, Zhuzhen

AU - Wang, May Yun

AU - Lin, Qian

AU - Field, Bianca

AU - Sun, Xue Nan

AU - Li, Guannan

AU - Ekane, Mbolle

AU - Onodera, Toshiharu

AU - Li, Na

AU - Zhu, Yi

AU - Kusminski, Christine M.

AU - Hinds, Terry D.

AU - Scherer, Philipp E.

PY - 2025/1/28

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N2 - Hepatic stellate cells (HSCs) are key drivers of local fibrosis. Adiponectin, conventionally thought of as an adipokine, is also expressed in quiescent HSCs. However, the impact of its local expression on the progression of liver fibrosis remains unclear. We recently generated a transgenic mouse line (Lrat-rtTA) that expresses the doxycycline-responsive transcriptional activator rtTA under the control of the HSC-specific lecithin retinol acyltransferase (Lrat) promoter, which enables us to specifically and inducibly overexpress or eliminate genes in these cells. The inducible elimination of HSCs protects mice from methionine/choline-deficient (MCD) diet-induced liver fibrosis, confirming their causal involvement in fibrosis development. We generated HSC-specific adiponectin overexpression and null models that demonstrate that HSC-specific adiponectin overexpression dramatically reduces liver fibrosis, whereas HSC-specific adiponectin elimination accelerates fibrosis progression. We identify a local adiponectin-peroxisome proliferator-activated receptor gamma (PPARγ) axis in HSCs that exerts a marked influence on the progression of local fibrosis, independent of circulating adiponectin derived from adipocytes.

AB - Hepatic stellate cells (HSCs) are key drivers of local fibrosis. Adiponectin, conventionally thought of as an adipokine, is also expressed in quiescent HSCs. However, the impact of its local expression on the progression of liver fibrosis remains unclear. We recently generated a transgenic mouse line (Lrat-rtTA) that expresses the doxycycline-responsive transcriptional activator rtTA under the control of the HSC-specific lecithin retinol acyltransferase (Lrat) promoter, which enables us to specifically and inducibly overexpress or eliminate genes in these cells. The inducible elimination of HSCs protects mice from methionine/choline-deficient (MCD) diet-induced liver fibrosis, confirming their causal involvement in fibrosis development. We generated HSC-specific adiponectin overexpression and null models that demonstrate that HSC-specific adiponectin overexpression dramatically reduces liver fibrosis, whereas HSC-specific adiponectin elimination accelerates fibrosis progression. We identify a local adiponectin-peroxisome proliferator-activated receptor gamma (PPARγ) axis in HSCs that exerts a marked influence on the progression of local fibrosis, independent of circulating adiponectin derived from adipocytes.

KW - CP: Metabolism

KW - PPARγ

KW - adiponectin

KW - liver fibrosis

KW - obesity

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The adiponectin-PPARγ axis in hepatic stellate cells regulates liver fibrosis

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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