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HORMONES AND SIGNALING

PI3-kinase activity modulates apo B available for hepatic VLDL production in apobec-1^–/– mice

¹Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York; and Departments of ²Internal Medicine and ³Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri

Submitted 7 October 2005 ; accepted in final form 1 April 2006

Insulin regulates hepatic VLDL production by activation of phosphatidylinositide 3-kinase (PI3-kinase) which decreases apo B available for lipid assembly. The current study evaluated the dependence of the VLDL apolipoprotein B (apo B) pathway on PI3-kinase activity in vivo. VLDL production was examined in B100 only, apo B mRNA editing catalytic subunit 1 (apobec-1^–/–) mice, using the Triton WR 1339 method. Glucose injection suppressed VLDL triglyceride production by 28% in male and by 32% in female mice compared with saline-injected controls. When wortmannin was injected to inhibit PI3-kinase, VLDL triglyceride production was increased by 52% in males and by 89% in females, and VLDL B100 levels paralleled triglyceride changes. Pulse-chase experiments in primary mouse hepatocytes showed that wortmannin increased net freshly synthesized B100 availability by >35%. To test whether physiological insulin resistance produced equivalent effects to wortmannin, we studied male apobec-1^–/– mice who became hyperlipidemic on being fed a fructose-enriched diet. Fructose-fed apobec-1^–/– mice had significantly higher VLDL triglyceride and B100 production rates compared with chow-fed mice, and rates were refractile to glucose or wortmannin. Hepatic VLDL triglyceride and B100 production in wortmannin-injected chow-fed mice equaled that observed in fructose-fed mice. Together, results suggest in vivo and in vitro that wortmannin-sensitive PI3-kinases maintain a basal level of VLDL suppression that is sensitive to changes in activation and that can increase VLDL production when PI3-kinase is inhibited to levels similar to those induced by insulin resistance.

very low-density lipoprotein

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