Acute hepatic steatosis in mice by blocking β-oxidation does not reduce insulin sensitivity of very-low-density lipoprotein production
article
Accumulation of triglycerides (TG) in the liver is generally associated with hepatic insulin resistance. We questioned whether acute hepatic steatosis induced by pharmacological blockade of β-oxidation affects hepatic insulin sensitivity, i.e., insulin-mediated suppression of VLDL production and insulin-induced activation of phosphatidylinositol 3-kinase (PI3-kinase) and PKB. Tetradecylglycidic acid (TDGA), an inhibitor of carnitine palmitoyl transferase-1 (CPT1), was used for this purpose. Male C57BL/6J mice received 30 mg/kg TDGA or its solvent intraperitoneally and were subsequently fasted for 12 h. CPT1 inhibition resulted in severe microvesicular hepatic steatosis (19.9 ± 8.3 vs. 112.4 ± 25.2 nmol TG/mg liver, control vs. treated, P < 0.05) with elevated plasma nonesterified fatty acid (0.68 ± 0.25 vs. 1.21 ± 0.41 mM, P < 0.05) and plasma TG (0.39 ± 0.16 vs. 0.60 ± 0.10 mM, P < 0.05) concentrations. VLDL-TG production rate was not affected on CPT1 inhibition (74.9 ± 15.2 vs. 79.1 ± 12.8 μmol TG·kg<sup>-1</sup>·min<sup>-1</sup>, control vs. treated) although treated mice secreted larger VLDL particles (59.3 ± 3.6 vs. 66.6 ± 4.5 nm diameter, P < 0.05). Infusion of insulin under euglycemic conditions suppressed VLDL production rate in control and treated mice by 43 and 54%, respectively, with formation of smaller VLDL particles (51.2 ± 2.5 and 53.2 ± 2.8 nm diameter). Insulin-induced insulin receptor substrate (IRS)1- and IRS2-associated PI3-kinase activity and PKB-phosphorylation were not affected on TDGA treatment. In conclusion, acute hepatic steatosis caused by pharmacological inhibition of β-oxidation is not associated with reduced hepatic insulin sensitivity, indicating that hepatocellular fat content per se is not causally related to insulin resistance. Copyright © 2005 the American Physiological Society. Chemicals/CAS: carnitine palmitoyltransferase, 9068-41-1; insulin receptor substrate 1, 175335-32-7; insulin receptor substrate 2, 223747-03-3; insulin, 9004-10-8; phosphatidylinositol 3 kinase, 115926-52-8; protein kinase B, 148640-14-6; 1-Phosphatidylinositol 3-Kinase, EC 2.7.1.137; 2-tetradecylglycidic acid, 68170-97-8; Cholesterol, VLDL; Epoxy Compounds; Fatty Acids; Hypoglycemic Agents; Insulin, 11061-68-0; Protein-Serine-Threonine Kinases, EC 2.7.1.37; Proto-Oncogene Proteins c-akt, EC 2.7.1.37; Proto-Oncogene Proteins
Topics
Carnitine palmitoyl transferase-1Tetradecylglycidic acidTriglyceridesCarnitine palmitoyltransferaseCarnitine palmitoyltransferase inhibitorInsulin receptor substrate 1Insulin receptor substrate 2Phosphatidylinositol 3 kinaseProtein kinase BTetradecylglycidic acidTriacylglycerolUnclassified drugVery low density lipoproteinAnimal experimentAnimal modelAnimal tissueControlled studyDiet restrictionEnzyme activationEnzyme activityEnzyme inhibitionFatty acid oxidationInsulin infusionInsulin resistanceInsulin sensitivityLipoprotein synthesisMouseNonhumanProtein phosphorylationProtein secretion1-Phosphatidylinositol 3-KinaseAcute DiseaseAnimalsCholesterol, VLDLEpoxy CompoundsFatty AcidsFatty LiverHypoglycemic AgentsInsulinMaleMiceMice, Inbred C57BLOxidation-ReductionProtein-Serine-Threonine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-akt
TNO Identifier
280168
ISSN
01931857
Source
American Journal of Physiology - Gastrointestinal and Liver Physiology, 289(3), pp. G592-G598.
Pages
G592-G598
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