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Journal of Lipid Research, Vol. 46, 988-993, May 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Acute inhibition of hepatic ß-oxidation in APOE*3Leiden mice does not affect hepatic VLDL secretion or insulin sensitivity

Ilse Duivenvoorden^*,, Bas Teusink^1,*, Patrick C. N. Rensen^*,, Folkert Kuipers, Johannes A. Romijn^**, Louis M. Havekes^*,, and Peter J. Voshol^2,*,**

^* Netherlands Organization for Applied Scientific Research-Quality of Life, Gaubius Laboratory, Leiden, The Netherlands
Department of General Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands
^** Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands
Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
Center for Liver, Digestive, and Metabolic Diseases, Laboratory of Pediatrics, University Hospital Groningen, Groningen, The Netherlands

² To whom correspondence should be addressed. e-mail: p.j.voshol{at}lumc.nl

Hepatic VLDL and glucose production is enhanced in type 2 diabetes and associated with hepatic steatosis. Whether the derangements in hepatic metabolism are attributable to steatosis or to the increased availability of FA metabolites is not known. We used methyl palmoxirate (MP), an inhibitor of carnitine palmitoyl transferase I, to acutely inhibit hepatic FA oxidation and investigated whether the FAs were rerouted into VLDL secretion and whether this would affect hepatic glucose production. After an overnight fast, male APOE3*Leiden transgenic mice received an oral dose of 10 mg/kg MP. Administration of MP led to an 83% reduction in plasma ß-hydroxybutyrate (ketone body) levels compared with vehicle-treated mice (0.47 ± 0.07 vs. 2.81 ± 0.16 mmol/l, respectively; P < 0.01), indicative of impaired ketogenesis. Plasma FFA levels were increased by 32% and cholesterol and insulin levels were decreased by 17% and 50%, respectively, in MP-treated mice compared with controls. MP treatment led to a 30% increase in liver triglyceride (TG) content. Surprisingly, no effect on hepatic VLDL-TG production was observed between the groups at 8 h after MP administration. In addition, the capacity of insulin to suppress endogenous glucose production was unaffected in MP-treated mice compared with controls.

In conclusion, acute inhibition of FA oxidation increases hepatic lipid content but does not stimulate hepatic VLDL secretion or reduce insulin sensitivity.

Abbreviations: acc1, acetyl-coenzyme A carboxylase 1; apoB, apolipoprotein B; CPT1, carnitine palmitoyl transferase 1; dgat, acyl:diacylglycerol transferase; fas, fatty acid synthase; ß-HB, ß-hydroxybutyrate; hmgs, 3-hydroxy-3-methylglutaryl-coenzyme A synthase; mcad, medium-chain acyl coenzyme A; MP, methyl palmoxirate; MTP, microsomal triglyceride transfer protein; mttp, microsomal triglyceride transfer protein; ppar, peroxisome proliferator-activated receptor ; srebp1c, sterol regulatory element binding protein 1c; TG, triglyceride

Supplementary key words triglycerides • fatty acids • steatosis • glucose metabolism • very low density lipoprotein

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