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 (PPARg) axis in HSCs that exerts a marked influence on the progression of local fibrosis, independent of circulating adiponectin derived from adipocytes.

Document Type

Article

Publication Date

1-2025

Notes/Citation Information

© 2024 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.celrep.2024.115165

Funding Information

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.

Download

Share

COinS