J. Lipid Res. Neurobiology of Lipids (ISSN1683-5506)
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A more recent version of this article appeared on May 1, 2005

Papers In Press, published online ahead of print February 16, 2005
J. Lipid Res., doi:10.1194/jlr.M400505-JLR200
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Submitted on December 20, 2004
Revised on January 31, 2005
Accepted on February 14, 2005

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

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

Endocrinology and metabolic diseases, Leiden University Medical Center, Leiden NL-2300RC

Corresponding Author: P.J.Voshol{at}lumc.nl

The hepatic production of VLDL and glucose is enhanced in type 2 diabetes, a condition associated with hepatic steatosis. Whether or not the derangements in hepatic metabolism are due to steatosis itself, or to increased availability of fatty acid (FA) metabolites is not known. We used methyl palmoxirate (MP), an inhibitor of carnitine palmitoyl transferase I (CPTI), to acutely inhibit hepatic FA oxidation, and investigated whether the FA were subsequently rerouted into VLDL secretion and whether the altered FA status would affect the hepatic glucose production. After overnight fasting 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 to vehicle-treated mice (0.47 ± 0.07 vs. 2.81 ± 0.16 mmol/L, respectively, p<0.01), indicative for impaired ketogenesis. Plasma FFA levels were elevated by 32% and cholesterol and insulin levels were decreased by 17% and 50%, respectively, in MP-treated mice compared to controls. MP treatment led to a 30% increase in liver TG content. Surprisingly, no acute effect on hepatic VLDL-TG production was observed between both groups, 8 h after MP administration. In addition, the capacity of insulin to suppress endogenous glucose production was unaffected in MP-treated mice compared to controls. In conclusion, acute inhibition of FA oxidation increases hepatic lipid content but does not stimulate hepatic VLDL secretion or reduce insulin sensitivity.


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 Am. J. Physiol. Endocrinol. Metab.Home page
M. A. M. den Boer, P. J. Voshol, F. Kuipers, J. A. Romijn, and L. M. Havekes
Hepatic glucose production is more sensitive to insulin-mediated inhibition than hepatic VLDL-triglyceride production
Am J Physiol Endocrinol Metab, December 1, 2006; 291(6): E1360 - E1364.
[Abstract] [Full Text] [PDF]


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