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LIVER AND BILIARY TRACT

Acute hepatic steatosis in mice by blocking -oxidation does not reduce insulin sensitivity of very-low-density lipoprotein production

¹Center for Liver, Digestive, and Metabolic Diseases, Laboratory of Pediatrics, University Medical Center Groningen, Groningen; ²Department of Molecular Cell Biology; ³TNO Prevention and Health, and Departments of General Internal Medicine and Cardiology; and ⁴Department of Endocrinology and Diabetes, Leiden University Medical Center, Leiden, The Netherlands

Submitted 11 February 2005 ; accepted in final form 6 April 2005

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 -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 -oxidation is not associated with reduced hepatic insulin sensitivity, indicating that hepatocellular fat content per se is not causally related to insulin resistance.

tetradecylglycidic acid; triglycerides; carnitine palmitoyl transferase-1

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