Inhibition of p53 attenuates steatosis and liver injury in a mouse model of non-alcoholic fatty liver disease

Background 82 Aims: p53 and its transcriptional target miRNA34a have been implicated in the pathogenesis of fatty liver. We tested the efficacy of a p53 inhibitor, pifithrin-a p-nitro (PET) in attenuating steatosis, associated oxidative stress and apoptosis in a murine model of non-alcoholic fatty liver disease (NAFLD). Methods: C57BL/6 mice were fed a high-fat (HFD) or control diet for 8 weeks; PET or DMSO (vehicle) was administered three times per week. Markers of oxidative stress and apoptosis as well as mediators of hepatic fatty acid metabolism were assessed by immunohistochemistry, Western blot, real-time PCR, and biochemical assays. Results: PET administration suppressed HFD-induced weight gain, ALT elevation, steatosis, oxidative stress, and apoptosis. PET treatment blunted the HFD-induced upregulation of miRNA34a and increased SIRT1 expression. In the livers of HFD-fed, PET-treated mice, activation of the SIRT1/PGC1 alpha/PPAR alpha axis increased the expression of malonyl-CoA decarboxylase (MLYCD), an enzyme responsible for malonyl-CoA (mCoA) degradation. Additionally, the SIRT1/LKB1/AMPK pathway (upstream activator of MLYCD) was promoted by PET. Thus, induction of these two pathways by PET diminished the hepatic mCoA content by enhancing MLYCD expression and function. Since mCoA inhibits carnitine palmitoyltransferase 1 (CPT1), the decrease of hepatic mCoA in the PET-treated, HFD-fed mice increased CPT1 activity, favored fatty acid oxidation, and decreased steatosis. Additionally, we demonstrated that PET abrogated steatosis and promoted MLYCD expression in palmitoleic acid-treated human HepaRG cells. Conclusions: The p53 inhibitor PET diminished hepatic triglyceride accumulation and lipotoxicity in mice fed a HFD, by depleting mCoA and favoring the beta-oxidation of fatty acids. (C) 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.