Effect of hepatocyte-specific PPARgamma knock out with and without rosiglitazone treatment in hepatic gene expression of mice with diet-induced NASH

In this study we sought to determine if the knockout of hepatocyte PPARgamma expression alter transcriptomics of the livers of mice with diet-induced NASH, and if there was a hepatocyte-specific PPARgamma dependent regulation of gene expression in TZD treated mice. Specifically, adult PPARg floxed male mice were fed a high fat, cholesterol and fructose (HFCF) diet for 24 weeks. After this period of time, half of the mice were injected with AAV8-TBG-Cre to knockout PPARgamma in hepatocytes (KO mice). The other half of the mice were injected with AAV8-TBG-Null, and served as controls (C mice). A subset of PPARg floxed mice were fed a low fat, cholesterol and fructose (LFCF) diet, and they were injected with AAV8-TBG-Null to generate LFCF-controls. Two weeks after AAV8 injections, half of the HFCF-fed mice in each group (C and KO) were switched to a HFCF diet containing rosiglitazone maleate (TZD, 50mg/kg of diet) for eight additional weeks. Mice were kept in their respective diets for 8 additional weeks too. At the end of the study, the livers were collected to assess hepatic gene expression with RNA-seq (performed by Novogen, Inc.) There are five groups: Group 1, LFCF-fed control mice: LF-C (4 mice: PG-783, PG-784, PG-785, PG-787) Group 2, HFCF-fed control mice: HF-C (5 samples: PG-721, PG-777, PG-734, PG-764, PG-780) Group 3, HFCF-fed hepatocyte-specific PPARgamma knock out mice: HF-KO (5 samples: PG-722, PG-748, PG-750, PG-765, PG-781) Group 4, TZD treated HFCF-fed control mice: HF/TZD-C (5 samples: PG-728, PG-731, PG-753, PG-768, PG-774) Group 5, TZD-treated HFCF-fed hepatocyte-specific PPARgamma knock out mice: HF/TZD-KO (5 samples: PG-754, PG-763, PG-770, PG-772, PG-776). We have compared the gene expression levels between the following groups: - LF-C vs HF-C to assess the effect of HFCF diet (34 weeks) in the regulation of hepatic gene expression in control mice. - HF-C vs HF-KO, to assess the effect of hepatocyte-specific PPARgamma knockout for 10 weeks in mice that were fed a HFCF diet. - HF-C vs TZD/HF-C and HF-KO vs TZD/HF-KO to assess the effect that TZD (rosiglitazone maleate) has in the regulation of hepatic gene expression in control (C) and hepatocyte-specific PPARgamma knock out (KO) mice with HFCF-induced NASH, respectively. - TZD/HF-C vs TZD/HF-KO to assess the effect that hepatocyte PPARgamma knock out had in mice with HFCF-induced NASH treated with TZD. Readcounts and FPKM of each sample are included in the processed files (comparisons indicated above), along with the Log2 fold change, p-value and p-adjusted.