Print Email Facebook Twitter Acute hepatic steatosis in mice by blocking β-oxidation does not reduce insulin sensitivity of very-low-density lipoprotein production Title Acute hepatic steatosis in mice by blocking β-oxidation does not reduce insulin sensitivity of very-low-density lipoprotein production Author TNO Kwaliteit van Leven Grefhorst, A. Hoekstra, J. Derks, T.G.J. Ouwens, D.M. Baller, J.F.W. Havinga, R. Havekes, L.M. Romijn, J.A. Kuipers, F. Publication year 2005 Abstract 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-1·min-1, 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 188.8.131.52; 2-tetradecylglycidic acid, 68170-97-8; Cholesterol, VLDL; Epoxy Compounds; Fatty Acids; Hypoglycemic Agents; Insulin, 11061-68-0; Protein-Serine-Threonine Kinases, EC 184.108.40.206; Proto-Oncogene Proteins c-akt, EC 220.127.116.11; Proto-Oncogene Proteins Subject 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 To reference this document use: http://resolver.tudelft.nl/uuid:ca47c713-370e-4be2-a1cc-af406cc54fba DOI https://doi.org/10.1152/ajpgi.00063.2005 TNO identifier 280168 ISSN 0193-1857 Source American Journal of Physiology - Gastrointestinal and Liver Physiology, 289 (289), G592-G598 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.