Acute inhibition of hepatic β-oxidation in APOE*3Leiden mice does not affect hepatic VLDL secretion or insulin sensitivity
article
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 β-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. Copyright © 2005 by the American Society for Biochemistry and Molecular Biology, Inc. Chemicals / CAS: 3 hydroxybutyrate dehydrogenase, 9028-38-0; cholesterol, 57-88-5; insulin, 9004-10-8; palmoxiric acid, 68170-97-8, 81556-15-2; apolipoprotein E3 (Leidein); Apolipoprotein E3; Apolipoproteins E; Fatty Acids, Nonesterified; Lipoproteins, VLDL; RNA, Messenger
Topics
Biomedical ResearchFatty acidsGlucose metabolismSteatosisTriglyceridesVery low density lipoprotein3 hydroxybutyrate dehydrogenasecarnitine palmitoyltransferase inhibitorcholesterolinsulinpalmoxiric acidtriacylglycerolvery low density lipoproteinapolipoprotein Eapolipoprotein E3apolipoprotein E3 (Leidein)fatty acidmessenger RNAanalytic methodanimal cellanimal experimentarticlecholesterol blood levelcomparative studycontrolled studyfatty acid oxidationgluconeogenesisinsulin blood levelinsulin sensitivityketogenesismousenonhumantransgenic mouseanimalbloodgeneticsinsulin resistancemetabolismoxidation reduction reactionphysiologysecretionAnimalsApolipoprotein E3Apolipoproteins EFatty Acids, NonesterifiedInsulin ResistanceLipoproteins, VLDLLiverMaleMiceMice, TransgenicOxidation-ReductionRNA, Messenger
TNO Identifier
239010
ISSN
00222275
Source
Journal of Lipid Research, 46(5), pp. 988-993.
Pages
988-993