title: Inhibition of p53 attenuates steatosis and liver injury in a mouse model of non-alcoholic fatty liver disease.
abstract: OBJECTIVE
  p53 and its transcriptional target miRNA34a have been implicated in the pathogenesis of fatty liver. We tested the efficacy of a p53 inhibitor, pifithrin-α p-nitro (PFT) 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; PFT 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
  PFT administration suppressed HFD-induced weight gain, ALT elevation, steatosis, oxidative stress, and apoptosis. PFT treatment blunted the HFD-induced upregulation of miRNA34a and increased SIRT1 expression. In the livers of HFD-fed, PFT-treated mice, activation of the SIRT1/PGC1α/PPARα 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 PFT. Thus, induction of these two pathways by PFT 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 PFT-treated, HFD-fed mice increased CPT1 activity, favored fatty acid oxidation, and decreased steatosis. Additionally, we demonstrated that PFT abrogated steatosis and promoted MLYCD expression in palmitoleic acid-treated human HepaRG cells.
  
  
  CONCLUSIONS
  The p53 inhibitor PFT diminished hepatic triglyceride accumulation and lipotoxicity in mice fed a HFD, by depleting mCoA and favoring the β-oxidation of fatty acids.
authors.affiliation: Division of Gastroenterology & Liver Research Center, Warren Alpert Medical School of Brown University and Rhode Island Hospital, Providence, RI 02903, USA. Zoltan_Derdak@brown.edu
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Derdak
authors.forename: Kristine A
authors.initials: KA
authors.lastname: Villegas
authors.forename: Ragheb
authors.initials: R
authors.lastname: Harb
authors.forename: Annie M
authors.initials: AM
authors.lastname: Wu
authors.forename: Aryanna
authors.initials: A
authors.lastname: Sousa
authors.forename: Jack R
authors.initials: JR
authors.lastname: Wands
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D052160:Benzothiazoles / Q000494:pharmacology*; D002460:Cell Line; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008316:Malonyl Coenzyme A / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D065626:Non-alcoholic Fatty Liver Disease; D018384:Oxidative Stress / Q000187:drug effects; D014050:Toluene / Q000031:analogs & derivatives* / Q000494:pharmacology; D014280:Triglycerides / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects
chemical_list: D052160:Benzothiazoles; D005227:Fatty Acids; C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; D014280:Triglycerides; D016159:Tumor Suppressor Protein p53; D014050:Toluene; D008316:Malonyl Coenzyme A; C121565:pifithrin; D000410:Alanine Transaminase