Abstract | BACKGROUND & AIMS: METHODS: OSR1/Osr1 expression patterns were compared in normal and NASH patients and mouse livers. NASH was established and compared between hepatocyte-specific Osr1 knockout (Osr1ΔHep), macrophage-specific Osr1 knockout (Osr1ΔMφ), and wild-type (Osr1F) mice fed with 3 different chronic obesogenic diets and methionine choline-deficient diet. Using genetic and therapeutic strategies in vitro and in vivo, the downstream targets of Osr1 and the associated mechanisms in inflammation-induced NASH were established. RESULTS: Osr1 was expressed in both hepatocytes and macrophages and exhibited different expression patterns in NASH. In NAFLD and NASH murine models, deleting Osr1 in myeloid cells (Osr1ΔMφ), but not hepatocytes, aggravated steatohepatitis with pronounced liver inflammation. Myeloid Osr1 deletion resulted in a polarization switch toward a pro-inflammatory phenotype associated with reduced oxidative phosphorylation activity. These inflamed Osr1ΔMφ macrophages promoted steatosis and inflammation in hepatocytes via cytokine secretion. We identified 2 downstream transcriptional targets of Osr1, c-Myc, and PPARγ and established the Osr1-PPARγ cascade in macrophage polarization and liver inflammation by genetic study and rosiglitazone treatment in vivo. We tested a promising intervention strategy targeting Osr1-PPARγ by AAV8L-delivered Osr1 expression or rosiglitazone that significantly repressed NAFLD/NASH progression in Osr1F and Osr1ΔMφ mice. CONCLUSIONS: Myeloid Osr1 mediates liver immune homeostasis and disrupting Osr1 aggravates the progression of NAFLD/NASH.
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Authors | Lin Liu, Yi Zhou, Zhimin Liu, Jiangyuan Li, Linghao Hu, Leya He, Guannan Gao, Brian Kidd, Alexandra Walsh, Rulang Jiang, Chaodong Wu, Ke Zhang, Linglin Xie |
Journal | Cellular and molecular gastroenterology and hepatology
(Cell Mol Gastroenterol Hepatol)
Vol. 15
Issue 5
Pg. 1117-1133
( 2023)
ISSN: 2352-345X [Electronic] United States |
PMID | 36581078
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Copyright | Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved. |
Chemical References |
- PPAR gamma
- Rosiglitazone
- Osr1 protein, mouse
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Topics |
- Animals
- Mice
- Hepatitis
(pathology)
- Inflammation
(pathology)
- Macrophages
(metabolism)
- Non-alcoholic Fatty Liver Disease
(pathology)
- PPAR gamma
(metabolism)
- Rosiglitazone
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