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

• Published in: American journal of physiology: Gastrointestinal and liver physiology 2006-09, Vol.291 (3), p.G382-G388
• Main Authors: Chirieac, Doru V, Davidson, Nicholas O, Sparks, Charles E, Sparks, Janet D
• Format: Article
• Language: English
• Subjects: Animals; APOBEC-1 Deaminase; Apolipoproteins B - metabolism; Biological Availability; Cholesterol, VLDL - metabolism; Cytidine Deaminase - genetics; Cytidine Deaminase - metabolism; Enzyme Activation; Feedback - physiology; Female; Liver - metabolism; Male; Metabolic Clearance Rate; Mice; Mice, Knockout; Phosphatidylinositol 3-Kinases - metabolism
• ISSN: 0193-1857; 1522-1547
• DOI: 10.1152/ajpgi.00472.2005

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.