Publication Date
1-28-2025
Journal
Cell Reports
DOI
10.1016/j.celrep.2024.115165
PMID
39792554
PMCID
PMC11839304
PubMedCentral® Posted Date
2-19-2025
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Keywords
Adiponectin, Humans, Hepatic Stellate Cells, Cell Line, Animals, Mice, Liver Cirrhosis, Animal Feed, Methionine, Choline, Endoplasmic Reticulum Stress, PPAR gamma, Gene Expression Regulation, Disease Progression
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.
Graphical Abstract
Included in
Biochemical Phenomena, Metabolism, and Nutrition Commons, Community Health and Preventive Medicine Commons, Dietetics and Clinical Nutrition Commons, Neurosciences Commons, Nutrition Commons, Pediatrics Commons
