Acute hepatic steatosis in mice by blocking beta-oxidation does not reduce insulin sensitivity of very-low-density lipoprotein production.
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 beta-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 mumol 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 beta-oxidation is not associated with reduced hepatic insulin sensitivity, indicating that hepatocellular fat content per se is not causally related to insulin resistance.
Grefhorst
Aldo
A
Center for Liver, Digestive and Metabolic Diseases, Laboratory of Pediatrics, Univ. Medical Center Groningen, Groningen, The Netherlands. A.Grefhorst@med.umcg.nl
Hoekstra
Jildou
J
Derks
Terry G J
TG
Ouwens
D Margriet
DM
Baller
Julius F W
JF
Havinga
Rick
R
Havekes
Louis M
LM
Romijn
Johannes A
JA
Kuipers
Folkert
F
D000208:Acute Disease; D000818:Animals; D015243:Cholesterol, VLDL / Q000096:biosynthesis*; D004852:Epoxy Compounds / Q000494:pharmacology; D005227:Fatty Acids / Q000494:pharmacology; D005234:Fatty Liver / Q000209:etiology / Q000503:physiopathology* / Q000662:veterinary; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt
D015243:Cholesterol, VLDL; D004852:Epoxy Compounds; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C021756:2-tetradecylglycidic acid