Saturday, May 17, 2025
5/17/2025
PPARgamma-regulated mechanisms in hepatocytes that promote NAFLD - Abstract of parent grant - R01DK131038 Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease with a prevalence of 25% in the general population. NAFLD is strongly associated with type 2 diabetes, where it shows a prevalence up to 80%, and a strong progression to non-alcoholic steatohepatitis (NASH, and advance stage of NAFLD). To date, there are no FDA-approved pharmacological treatments for NAFLD. However, thiazolidinediones (TZD), which are effective anti-diabetogenic drugs, may be used to treat NAFLD/NASH. Specifically, TZD activate peroxisome proliferator-activated receptor gamma (PPARg) in adipocytes, macrophages, and hepatic stellate cells (HSC), and they should reduce insulin resistance, inflammation, and fibrogenesis, respectively. Despite having some positive effects, TZD are not currently used to treat NASH, and it is possible that their true potential as anti- NASH drugs are indeed reduced by direct negative actions on hepatocyte function. In fact, our preliminary studies show that hepatocyte PPARg is a relevant factor in the regulation of hepatic gene expression that contributes to the progression of NASH, and reduces the therapeutic effects of TZD in the liver of mice with NASH. In this proposal, we hypothesize that hepatocyte PPARg is a negative regulator of phosphatidylethanolamine methyltransferase (PEMT) and betaine-homocysteine methyltransferase (BHMT), disrupts methionine metabolism, and promotes NASH. In our Aim 1, we will define the contribution of hepatocyte PEMT and BHMT in the TZD-mediated reversal of NASH. Specifically, we will restore the expression of PEMT or BHMT with adeno-associated viruses in PPARg-intact mice after the development of NASH and treat these mice with TZD to reverse NASH. Also, hepatocyte PEMT and BHMT will be restored in mice with hepatocyte- specific loss of PPARg expression without a TZD treatment. This aim will show how PEMT and BHMT improve liver health, and reduce steatosis, inflammation and fibrosis to enhance the therapeutic actions of TZD in the reversal of NASH. In aim 2, we will determine if PPARg directly disrupts the metabolism of methionine in hepatocytes. Briefly, we will use targeted metabolomics in mouse and human primary hepatocytes or in perfused livers of controls and mice with hepatocyte-specific loss of PPARg expression that are treated with TZD. These experiments will identify how TZD alters the use of methionine in hepatocytes, and contributes, in a hepatocyte- specific PPARg-dependent manner, to sustain steatosis, inflammation and fibrosis despite the positive actions of TZD on adipocytes, macrophages, and HSC. Overall, in this proposal we will describe how hepatocyte-specific PPARg negatively regulates methionine metabolism to promote NAFLD, and to limit the potential of TZD as a therapy for NASH. The outcomes of this project will lead us to develop therapeutic strategies that enhance the use of TZD, and to develop new treatments for NAFLD and the care of NASH patients.
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