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 Jr; Philipp E Scherer

doi:10.1016/j.celrep.2024.115165

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

Cell Rep. 2025 Jan 9;44(1):115165. doi: 10.1016/j.celrep.2024.115165. Online ahead of print.

Authors

Shangang Zhao¹, Qingzhang Zhu², Wang-Hsin Lee³, Jan-Bernd Funcke⁴, Zhuzhen Zhang⁵, May-Yun Wang⁴, Qian Lin⁴, Bianca Field⁴, Xue-Nan Sun⁴, Guannan Li⁶, Mbolle Ekane⁶, Toshiharu Onodera⁷, Na Li⁸, Yi Zhu⁹, Christine M Kusminski⁴, Terry D Hinds Jr³, Philipp E Scherer¹⁰

Affiliations

¹ Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; Sam and Ann Barshop Institute for Longevity and Aging Studies, Division of Endocrinology, Department of Medicine and Department of Cellular & Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
² Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, KY 40508, USA.
³ Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA.
⁴ Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁵ Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; College of Life Sciences, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan 430072, China.
⁶ Sam and Ann Barshop Institute for Longevity and Aging Studies, Division of Endocrinology, Department of Medicine and Department of Cellular & Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
⁷ Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Adipose Management, Osaka University Graduate School of Medicine, Osaka, Japan.
⁸ Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin 300052, China.
⁹ Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁰ Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: [email protected].

PMID: 39792554
DOI: 10.1016/j.celrep.2024.115165

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.