The adiponectin-PPARγ axis in hepatic stellate cells regulates liver fibrosis
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.
Authors
- Yi Zhu (ORCID: https://orcid.org/0000-0003-1650-1363)
- Bianca C. Field (ORCID: https://orcid.org/0000-0002-0297-949X)
- Zhuzhen Zhang (ORCID: https://orcid.org/0000-0001-6787-3920)
- Christine M. Kusminski
- Qian Lin
- Toshiharu Onodera (ORCID: https://orcid.org/0000-0002-4439-0077)
- Terry D. Hinds (ORCID: https://orcid.org/0000-0002-7599-1529)
- Jan‐Bernd Funcke (ORCID: https://orcid.org/0000-0002-2596-3167)
- Qingzhang Zhu (ORCID: https://orcid.org/0000-0001-9382-8517)
- Wang‐Hsin Lee (ORCID: https://orcid.org/0000-0001-5258-8318)
- Philipp E. Scherer (ORCID: https://orcid.org/0000-0003-0680-3392)
- Shangang Zhao (ORCID: https://orcid.org/0000-0002-9209-8206)
- Na Li (ORCID: https://orcid.org/0000-0002-0604-6312)
- Guannan Li (ORCID: https://orcid.org/0000-0002-6070-5008)
- Xue-Nan Sun
- May-Yun Wang
- Mbolle Ekane
Institutions
- University of Kentucky (US)
- The University of Texas at San Antonio Health Science Center (US)
- Tianjin Medical University General Hospital (CN)
- Wuhan University (CN)
- Southwestern Medical Center (US)
- Children's Nutrition Research Center at Baylor College of Medicine (US)
- The University of Texas Southwestern Medical Center (US)
- The University of Osaka (JP)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-01-01
- DOI
- https://doi.org/10.1016/j.celrep.2024.115165
- Citations
- 14
- Primary Topic
- Liver Disease Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 18.96
Funders
- American Heart Association
- Max and Minnie Tomerlin Voelcker Fund
- National Institutes of Health
- Merck Sharp and Dohme
- National Institute on Aging
- National Institute of Diabetes and Digestive and Kidney Diseases