HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 294/5/E969    most recent 00497.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Stefanovic-Racic, M. Articles by O'Doherty, R. M. PubMed PubMed Citation Articles by Stefanovic-Racic, M. Articles by O'Doherty, R. M.

A moderate increase in carnitine palmitoyltransferase 1a activity is sufficient to substantially reduce hepatic triglyceride levels

¹Department of Medicine, Division of Endocrinology and ²Department of Molecular Genetics and Biochemistry, University of Pittsburgh, and ³University of Pittsburgh/Carnegie Mellon University Medical Scientist Training Program, Pittsburgh, Pennsylvania

Submitted 31 July 2007 ; accepted in final form 17 March 2008

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 β-galactosidase (Adv-β-gal) or carnitine palmitoyltransferase 2 (Adv-CPT-2). Overexpression of CPT-1a increased the rate of β-oxidation and ketogenesis by 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-β-gal, or Adv-CPT-2. Hepatic CPT-1a activity was increased by 46%, and the rate of fatty acid oxidation was increased by 44% in lean and 36% in obese CPT-1a-overexpressing animals compared with Adv-CPT-2- or Adv-β-gal-treated rats. Similar to observations in vitro, liver TG content was reduced by 37% (lean) and 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.

fatty liver