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

Abstract

Stefanovic-Racic M, Perdomo G, Mantell BS, Sipula IJ, Brown NF, O'Doherty RM. A moderate increase in carnitine palmitoyltransferase 1a activity is sufficient to substantially reduce hepatic triglyceride levels. Am J Physiol Endocrinol Metab 294: E969-E977, 2008. First published March 18, 2008 doi:10.1152/ajpendo.00497.2007.-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 ␤-galactosidase (Adv-␤-gal) or carnitine palmitoyltransferase 2 (Adv-CPT-2). Overexpression of CPT-1a increased the rate of ␤-oxidation and ketogenesis by ϳ70%, 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-␤-gal, or Adv-CPT-2. Hepatic CPT-1a activity was increased by ϳ46%, and the rate of fatty acid oxidation was increased by ϳ44% in lean and ϳ36% in obese CPT-1a-overexpressing animals compared with Adv-CPT-2-or Adv-␤-gal-treated rats. Similar to observations in vitro, liver TG content was reduced by ϳ37% (lean) and ϳ69% (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 NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) represents a spectrum of liver abnormalities with an estimated prevalence between 14 and 24% in the general population (4). Furthermore, NAFLD is present in the majority of patients with metabolic syndrome and type 2 diabetes mellitus (DM) (29) and is strongly associated with insulin resistance (38) characterized by the inability of insulin to control hepatic gluconeogenesis (28). Although most patients with NAFLD have asymptomatic fatty liver, the condition predisposes toward the development of steatohepatitis, cirrhosis, and hepatocellular carcinoma. Furthermore, hepatic lipid accumulation is associated with a more atherogenic lipid profile (25), including hypertriglyceridemia, a higher plasma concentration of...

Dietary Medium-Chain Triglycerides Attenuate Hepatic Lipid Deposition in Growing Rats with Protein Malnutrition

“…These developmental changes in CPT1a protein were closely related to the changes in its mRNA levels (15). A moderate increase in CPT1a is sufficient to stimulate fatty acid oxidation and substantially reduce hepatic triglyceride accumulation in rats (16). In the present study, both the decreased level of hepatic CPT1a mRNA and development of fatty liver were observed in growing rats fed low-protein diets.…”

Protein kinase STK25 controls lipid partitioning in hepatocytes and correlates with liver fat content in humans

“…Increased hepatic mitochondrial oxidation has been observed in patients and rodents with fatty liver [23,24], which likely reflects a metabolic adaptation to elevated lipid burden to limit further fat accumulation. Indeed, the development of fatty liver and hepatic insulin resistance in response to high-fat feeding in rats can be prevented by increasing mitochondrial β-oxidation [25][26][27][28]. Furthermore, a primary defect in mitochondrial β-oxidation capacity in mice has been shown to result in liver steatosis and hepatic insulin resistance [29].…”

Fibrates Reduce Triacylglycerol Content by Upregulating Adipose Triglyceride Lipase in the Liver of Rats

“…The treatments were the same as those described in the legend to Fig. 2, A, sufficient to substantially reduce hepatic TAG (30). Therefore, it is likely that mitochondrial b-oxidation, in particular CPT1a, plays a greater role in fatty acid degradation in the liver of fibrate-treated rats, whereas the upregulation of Acox1, a rate-limiting enzyme of peroxisomal b-oxidation, by fibrates plays a physiologically less dominant role in fatty acid catabolism.…”