title: A moderate increase in carnitine palmitoyltransferase 1a activity is sufficient to substantially reduce hepatic triglyceride levels.
abstract: Nonalcoholic fatty liver disease (NAFLD), hypertriglyceridemia, and elevated free fatty acids are present in the majority of patients with metabolic syndrome and type 2 diabetes mellitus and are strongly associated with hepatic insulin resistance. In the current study, we tested the hypothesis that an increased rate of fatty acid oxidation in liver would prevent the potentially harmful effects of fatty acid elevation, including hepatic triglyceride (TG) accumulation and elevated TG secretion. Primary rat hepatocytes were transduced with adenovirus encoding carnitine palmitoyltransferase 1a (Adv-CPT-1a) or control adenoviruses encoding either beta-galactosidase (Adv-beta-gal) or carnitine palmitoyltransferase 2 (Adv-CPT-2). Overexpression of CPT-1a increased the rate of beta-oxidation and ketogenesis by approximately 70%, whereas esterification of exogenous fatty acids and de novo lipogenesis were unchanged. Importantly, CPT-1a overexpression was accompanied by a 35% reduction in TG accumulation and a 60% decrease in TG secretion by hepatocytes. There were no changes in secretion of apolipoprotein B (apoB), suggesting the synthesis of smaller, less atherogenic VLDL particles. To evaluate the effect of increasing hepatic CPT-1a activity in vivo, we injected lean or obese male rats with Adv-CPT-1a, Adv-beta-gal, or Adv-CPT-2. Hepatic CPT-1a activity was increased by approximately 46%, and the rate of fatty acid oxidation was increased by approximately 44% in lean and approximately 36% in obese CPT-1a-overexpressing animals compared with Adv-CPT-2- or Adv-beta-gal-treated rats. Similar to observations in vitro, liver TG content was reduced by approximately 37% (lean) and approximately 69% (obese) by this in vivo intervention. We conclude that a moderate stimulation of fatty acid oxidation achieved by an increase in CPT-1a activity is sufficient to substantially reduce hepatic TG accumulation both in vitro and in vivo. Therefore, interventions that increase CPT-1a activity could have potential benefits in the treatment of NAFLD.
authors: Department of Medicine, Division of Endocrinology, University of Pittsburg, Pittsburgh, PA, USA. stefanovicracicm@upmc.edu
authors: Maja
authors: M
authors: Stefanovic-Racic
authors: German
authors: G
authors: Perdomo
authors: Benjamin S
authors: BS
authors: Mantell
authors: Ian J
authors: IJ
authors: Sipula
authors: Nicholas F
authors: NF
authors: Brown
authors: Robert M
authors: RM
authors: O'Doherty
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D002469:Cell Separation; D002478:Cells, Cultured; D004032:Diet; D004041:Dietary Fats / Q000494:pharmacology; D004952:Esters / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015151:Immunoblotting; D007657:Ketone Bodies / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology; D008099:Liver / Q000201:enzymology* / Q000378:metabolism*; D008297:Male; D010084:Oxidation-Reduction; D010168:Palmitates / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D001055:Apolipoproteins B; D001786:Blood Glucose; D004041:Dietary Fats; D004952:Esters; D005227:Fatty Acids; D007657:Ketone Bodies; D010168:Palmitates; D014280:Triglycerides; D002334:Carnitine O-Palmitoyltransferase