title: Insulin-stimulated degradation of apolipoprotein B100: roles of class II phosphatidylinositol-3-kinase and autophagy.
abstract: Both in humans and animal models, an acute increase in plasma insulin levels, typically following meals, leads to transient depression of hepatic secretion of very low density lipoproteins (VLDL). One contributing mechanism for the decrease in VLDL secretion is enhanced degradation of apolipoprotein B100 (apoB100), which is required for VLDL formation. Unlike the degradation of nascent apoB100, which occurs in the endoplasmic reticulum (ER), insulin-stimulated apoB100 degradation occurs post-ER and is inhibited by pan-phosphatidylinositol (PI)3-kinase inhibitors. It is unclear, however, which of the three classes of PI3-kinases is required for insulin-stimulated apoB100 degradation, as well as the proteolytic machinery underlying this response. Class III PI3-kinase is not activated by insulin, but the other two classes are. By using a class I-specific inhibitor and siRNA to the major class II isoform in liver, we now show that it is class II PI3-kinase that is required for insulin-stimulated apoB100 degradation in primary mouse hepatocytes. Because the insulin-stimulated process resembles other examples of apoB100 post-ER proteolysis mediated by autophagy, we hypothesized that the effects of insulin in autophagy-deficient mouse primary hepatocytes would be attenuated. Indeed, apoB100 degradation in response to insulin was significantly impaired in two types of autophagy-deficient hepatocytes. Together, our data demonstrate that insulin-stimulated apoB100 degradation in the liver requires both class II PI3-kinase activity and autophagy.
authors.affiliation: Department of Medicine, New York University School of Medicine, New York, New York, USA.
authors.forename: Ursula
authors.initials: U
authors.lastname: Andreo
authors.forename: Liang
authors.initials: L
authors.lastname: Guo
authors.forename: Doru V
authors.initials: DV
authors.lastname: Chirieac
authors.forename: Ana C
authors.initials: AC
authors.lastname: Tuyama
authors.forename: Emilie
authors.initials: E
authors.lastname: Montenont
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Brodsky
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fisher
mesh_terms: D000818:Animals; D053299:Apolipoprotein B-100 / Q000378:metabolism*; D001343:Autophagy; D058541:Class II Phosphatidylinositol 3-Kinases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D008079:Lipoproteins, VLDL / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D059748:Proteolysis / Q000187:drug effects
chemical_list: D053299:Apolipoprotein B-100; D007328:Insulin; D008079:Lipoproteins, VLDL; D058541:Class II Phosphatidylinositol 3-Kinases