Hepatic VLDL Production in ob/ob Mice Is Not Stimulated by Massive De Novo Lipogenesis but Is Less Sensitive to the Suppressive Effects of Insulin

• Published in: Diabetes (New York, N.Y.) Vol. 52; no. 5; pp. 1081 - 1089
• Main Authors: WIEGMAN, Coen H, BANDSMA, Robert H. J, OUWENS, Margriet, VAN DER SLUIJS, Fjodor H, HAVINGA, Rick, BOER, Theo, REIJNGOUD, Dirk-Jan, ROMIJN, Johannes A, KUIPERS, Folkert
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.05.2003
• Subjects: Adipose Tissue - metabolism; Animals; Apolipoprotein B-100; Apolipoproteins B - biosynthesis; Apolipoproteins B - drug effects; Base Sequence; Biological and medical sciences; Cholesterol - biosynthesis; Cholesterol Esters - biosynthesis; Development and progression; DNA Primers; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; Hyperinsulinism - metabolism; Insulin - pharmacology; Kinetics; Lipids - biosynthesis; Lipoproteins, VLDL - biosynthesis; Lipoproteins, VLDL - drug effects; Lipoproteins, VLDL - genetics; Liver - drug effects; Liver - metabolism; Low density lipoproteins; Measurement; Mice; Mice, Obese; Oligonucleotide Probes; Physiological aspects; Reference Values; Triglycerides - blood; Type 2 diabetes; Very low density lipoproteins; Netherlands
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.52.5.1081

Hepatic VLDL Production in ob / ob Mice Is Not Stimulated by Massive De Novo Lipogenesis but Is Less Sensitive to the Suppressive Effects of Insulin Coen H. Wiegman 1 , Robert H.J. Bandsma 1 , Margriet Ouwens 2 , Fjodor H. van der Sluijs 1 , Rick Havinga 1 , Theo Boer 1 , Dirk-Jan Reijngoud 1 , Johannes A. Romijn 3 and Folkert Kuipers 1 1 Groningen University Institute for Drug Exploration, Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics, University Hospital Groningen, Groningen, the Netherlands 2 Department of Molecular Cell Biology, University Hospital Leiden, Leiden, the Netherlands 3 Department of Endocrinology, University Hospital Leiden, Leiden, the Netherlands Abstract Type 2 diabetes in humans is associated with increased de novo lipogenesis (DNL), increased fatty acid (FA) fluxes, decreased FA oxidation, and hepatic steatosis. In this condition, VLDL production is increased and resistant to suppressive effects of insulin. The relationships between hepatic FA metabolism, steatosis, and VLDL production are incompletely understood. We investigated VLDL-triglyceride and -apolipoprotein (apo)-B production in relation to DNL and insulin sensitivity in female ob / ob mice. Hepatic triglyceride (5-fold) and cholesteryl ester (15-fold) contents were increased in ob / ob mice compared with lean controls. Hepatic DNL was increased ∼10-fold in ob / ob mice, whereas hepatic cholesterol synthesis was not affected. Basal rates of hepatic VLDL-triglyceride and -apoB100 production were similar between the groups. Hyperinsulinemic clamping reduced VLDL-triglyceride and -apoB100 production rates by ∼60% and ∼75%, respectively, in lean mice but only by ∼20% and ∼20%, respectively, in ob / ob mice. No differences in hepatic expression of genes encoding apoB and microsomal triglyceride transfer protein were found. Hepatic expression and protein phosphorylation of insulin receptor and insulin receptor substrate isoforms were reduced in ob / ob mice. Thus, strongly induced hepatic DNL is not associated with increased VLDL production in ob / ob mice, possibly related to differential hepatic zonation of apoB synthesis (periportal) and lipid accumulation (perivenous) and/or relatively low rates of cholesterogenesis. Insulin is unable to effectively suppress VLDL-triglyceride production in ob / ob mice, presumably because of impaired insulin signaling. Footnotes Address correspondence and reprint requests to Folkert Kuipers, Department of Pediatrics, Room Y2115 CMCIV, Hanzeplein 1, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands. E-mail: f.kuipers{at}med.rug.nl . Received for publication 16 June 2002 and accepted in revised form 29 January 2003. C.H.W. and R.H.J.B. contributed equally to this work. apo, apolipoprotein; CHREBP, carbohydrate responsive element–binding protein; DNL, de novo lipogenesis; FA, fatty acid; FFA, free fatty acid; IDL, intermediate-density lipoprotein; IR, insulin receptor; IRS, insulin receptor substrate; MIDA, mass isotopomer distribution analysis; PI3K, phosphatidylinositol 3-kinase; PPAR, peroxisome proliferator–activated receptor; SREBP, sterol regulatory element–binding protein; TG, triglyceride. DIABETES