Loss of Hepatocyte-Specific PPARγ Expression Ameliorates Early Events of Steatohepatitis in Mice Fed the Methionine and Choline-Deficient Diet

Abstract

The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. To date, there is not a specific and approved treatment for NAFLD yet, and therefore, it is important to understand the molecular mechanisms that lead to the progression of NAFLD. Methionine- and choline-deficient (MCD) diets are used to reproduce some features of NAFLD in mice. MCD diets increase the expression of hepatic peroxisome proliferator-activated receptor gamma (PPARγ, Pparg) and the fatty acid translocase (CD36, Cd36) which could increase hepatic fatty acid uptake and promote the progression of NAFLD in mice and humans. In this study, we assessed the contribution of hepatocyte-specific PPARγ and CD36 expression to the development of early events induced by the MCD diet. Specifically, mice with adult-onset, hepatocyte-specific PPARγ knockout with and without hepatocyte CD36 overexpression were fed a MCD diet for three weeks. Hepatocyte PPARγ and/or CD36 expression did not contribute to the development of steatosis induced by the MCD diet. However, the expression of inflammatory and fibrogenic genes seems to be dependent on the expression of hepatocyte PPARγ and CD36. The expression of PPARγ and CD36 in hepatocytes may be relevant in the regulation of some features of NAFLD and steatohepatitis.

Hepatocyte-Specific Loss of PPARγ Protects Mice From NASH and Increases the Therapeutic Effects of Rosiglitazone in the Liver

“…However, growing evidence supports a positive association between hepatocyte PPARγ and fibrosis. 30 , 34 , 36 In this sense, our unbiased transcriptomic analysis revealed that Pparg ΔHep had a major impact in the regulation of pathways related with inflammation and fibrogenesis rather than steatosis, which strongly suggests that the presence and activation of hepatocyte PPARγ may be relevant in the activation of non-parenchymal cells during the progression of NAFLD.…”

“…Our experimental approach showed that >90% of liver PPARγ expression is hepatocyte-specific. 18 , 30 Hepatic PPARγ expression is low in lean mice, but it increases upon feeding with a high-fat diet and contributes to the development of steatosis. 17 , 18 , 19 , 31 , 32 In mice with liver steatosis, a short-term treatment with a low dose of TZD, 50–100 mg rosiglitazone/kg of diet, which represents a daily dose of 3–5 mg/kg body weight, promotes steatosis in a hepatocyte PPARγ-dependent manner.…”

“…In addition, we published that Pparg ΔHep does not reduce steatosis in a model of DNL-mediated steatosis 37 or in a model of steatohepatitis induced by methionine- and choline-deficient diet, but rather, it reduces fibrosis. 30 Therefore, the steatogenic role of hepatocyte PPARγ and its contribution to the development of NASH is mouse model- and diet-dependent. However, growing evidence supports a positive association between hepatocyte PPARγ and fibrosis.…”

“…Pparg ΔHep mice were generated by injecting 100 μL saline containing 1.5 × 10 11 genome copies of AAV serotype 8 (AAV8) vectors that bear a thyroxine binding globulin (TBG)-driven Cre recombinase (AAV8-TBG-Cre; Penn Vector Core, University of Pennsylvania) in the lateral-tail vein of Pparg fl/fl mice. 18 , 30 We described the hepatocyte-specific expression of transgene delivered by AAV-TBG vectors previously. 18 , 51 A subset of Pparg fl/fl littermate mice injected with 1.5 × 10 11 genome copies of AAV8-TBG-Null generates controls.…”

Bergenin Attenuates Hepatic Fibrosis by Regulating Autophagy Mediated by the PPAR-γ/TGF-β Pathway

“…Peroxisome proliferator-activated receptor (PPAR) is a ligand-activated receptor belonging to the type II nuclear hormone receptor superfamily that includes PPAR- α , PPAR- β / δ , and PPAR- γ subtypes [ 3 , 4 ]. PPAR- γ is a key transcription factor of cell differentiation, which is closely related to fibrosis in important organs [ 5 , 6 ].…”