Hepatocyte-Specific Loss of PPARγ Protects Mice From NASH and Increases the Therapeutic Effects of Rosiglitazone in the Liver
| Autor: | Brian T. Layden, Samuel M Lee, Carolina M. Pusec, Andre Sarmento-Cabral, Grace Guzman, Jose Muratalla, Jose Cordoba-Chacon, Alberto Diaz-Ruiz, Gregory H Norris, Adam De Jesus |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine ip intraperitoneal Endogeny RC799-869 Type 2 diabetes Mice chemistry.chemical_compound AAV adeno-associated virus 0302 clinical medicine Non-alcoholic Fatty Liver Disease Receptor LFCF low fat cholesterol and fructose Original Research Mice Knockout DEG differential expressed gene NAS NAFLD Activity Score Gastroenterology SAM S-adenosylmethionine Diseases of the digestive system. Gastroenterology TG triglycerides medicine.anatomical_structure Hepatocyte Female 030211 gastroenterology & hepatology medicine.symptom Rosiglitazone NASH nonalcoholic steatohepatitis medicine.drug medicine.medical_specialty PPARγ peroxisome proliferator-activated receptor gamma Inflammation DNL de novo lipogenesis Diet High-Fat digestive system 03 medical and health sciences HFCF high fat cholesterol and fructose ALT alanine aminotransferase Internal medicine medicine Animals Hypoglycemic Agents Metabolomics PpargΔHep adult-onset hepatocyte-specific PPARγ knockout NMR nuclear magnetic resonance GO gene ontology AAV8-TBG-Cre Hepatology business.industry Cholesterol SAH S-adenosylhomocysteine nutritional and metabolic diseases Hcy homocysteine NASH Reversion medicine.disease TZD thiazolidinediones digestive system diseases PPAR gamma 030104 developmental biology Endocrinology chemistry Hepatocytes TGB thyroxine binding globulin NAFLD nonalcoholic fatty liver disease Steatosis business Methionine Metabolism |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology Cellular and Molecular Gastroenterology and Hepatology, Vol 11, Iss 5, Pp 1291-1311 (2021) |
| ISSN: | 2352-345X |
| Popis: | Background & Aims Nonalcoholic steatohepatitis (NASH) is commonly observed in patients with type 2 diabetes, and thiazolidinediones (TZD) are considered a potential therapy for NASH. Although TZD increase insulin sensitivity and partially reduce steatosis and alanine aminotransferase, the efficacy of TZD on resolving liver pathology is limited. In fact, TZD may activate peroxisome proliferator-activated receptor gamma (PPARγ) in hepatocytes and promote steatosis. Therefore, we assessed the role that hepatocyte-specific PPARγ plays in the development of NASH, and how it alters the therapeutic effects of TZD on the liver of mice with diet-induced NASH. 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. Graphical abstract |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|