Abstract | BACKGROUND & AIMS: METHODS: Hepatocyte-specific PPARγ expression was knocked out in adult mice before and after the development of NASH induced with a high fat, cholesterol, and fructose (HFCF) diet. RESULTS: HFCF diet increased PPARγ expression in hepatocytes, and rosiglitazone further activated PPARγ in hepatocytes of HFCF-fed mice in vivo and in vitro. Hepatocyte-specific loss of PPARγ reduced the progression of HFCF-induced NASH in male mice and increased the benefits derived from the effects of TZD on extrahepatic tissues and non-parenchymal cells. RNAseq and metabolomics indicated that HFCF diet promoted inflammation and fibrogenesis in a hepatocyte PPARγ-dependent manner and was associated with dysregulation of hepatic metabolism. Specifically, hepatocyte-specific loss of PPARγ plays a positive role in the regulation of methionine metabolism, and that could reduce the progression of NASH. CONCLUSIONS: Because of the negative effect of hepatocyte PPARγ in NASH, inhibition of mechanisms promoted by endogenous PPARγ in hepatocytes may represent a novel strategy that increases the efficiency of therapies for NAFLD.
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Authors | Samuel M Lee, Carolina M Pusec, Gregory H Norris, Adam De Jesus, Alberto Diaz-Ruiz, Jose Muratalla, Andre Sarmento-Cabral, Grace Guzman, Brian T Layden, Jose Cordoba-Chacon |
Journal | Cellular and molecular gastroenterology and hepatology
(Cell Mol Gastroenterol Hepatol)
Vol. 11
Issue 5
Pg. 1291-1311
( 2021)
ISSN: 2352-345X [Electronic] United States |
PMID | 33444819
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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Copyright | Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved. |
Chemical References |
- Hypoglycemic Agents
- PPAR gamma
- Rosiglitazone
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Topics |
- Animals
- Diet, High-Fat
- Female
- Hepatocytes
(drug effects, metabolism)
- Hypoglycemic Agents
(pharmacology)
- Inflammation
(etiology, metabolism, pathology, prevention & control)
- Male
- Mice
- Mice, Knockout
- Non-alcoholic Fatty Liver Disease
(etiology, metabolism, pathology, prevention & control)
- PPAR gamma
(antagonists & inhibitors, physiology)
- Rosiglitazone
(pharmacology)
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