1. Hepatocyte-Specific Loss of PPARγ Protects Mice From NASH and Increases the Therapeutic Effects of Rosiglitazone in the Liver
- Author
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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, and Adam De Jesus
- Subjects
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 - Abstract
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
- Published
- 2021
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