PI3-kinase activity modulates apo B available for hepatic VLDL production in apobec-1-/- mice.
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.
Chirieac
Doru V
DV
Dept. of Pathology and Laboratory Medicine, Univ. of Rochester School of Medicine & Dentistry, P.O. Box 626, 601 Elmwood Ave., Rochester, New York 14642, USA.
Davidson
Nicholas O
NO
Sparks
Charles E
CE
Sparks
Janet D
JD
D000071479:APOBEC-1 Deaminase; D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism*; D001682:Biological Availability; D015243:Cholesterol, VLDL / Q000378:metabolism*; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D005246:Feedback / Q000502:physiology; D005260:Female; D008099:Liver / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*
D001055:Apolipoproteins B; D015243:Cholesterol, VLDL; D019869:Phosphatidylinositol 3-Kinases; D000071479:APOBEC-1 Deaminase; C000605090:Apobec1 protein, mouse; D003564:Cytidine Deaminase