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.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is becoming the main cause of chronic liver disease, and it has a high prevalence in the general population worldwide [1]
In order to assess the role of hepatocyte PPARγ in the early events of steatohepatitis induced by methionine- and choline-deficient (MCD) diet, we have knocked out the expression of PPARγ only in hepatocytes of adult mice and fed the mice with MCD diet for only three weeks
We altered the expression of PPARγ and CD36 in hepatocytes of adult Ppargfl/fl mice, but that did not alter the effect of MCD diets on adiposity or plasma lipids
Summary
Nonalcoholic fatty liver disease (NAFLD) is becoming the main cause of chronic liver disease, and it has a high prevalence in the general population worldwide [1]. Nonalcoholic steatohepatitis (NASH) is the advance pathological state of NAFLD, and it is characterized by hepatic inflammation and liver damage with or without fibrosis. There are no FDA-approved medical treatments for NAFLD, and the prevalence of this disease is expected to keep increasing [2, 3]. Different dietary mouse models are used to reproduce some of the features of NASH, and among them is the model of steatohepatitis induced by the methionine- and choline-deficient (MCD) diet. MCD diets induce quickly some features of NASH due in part to an increase of hepatic fatty acid uptake [4,5,6], reduction of hepatic fatty acid oxidation [7], secretion of very-low-density lipoprotein (VLDL) [8], and glutathione production [9, 10]
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