Abstract 413: Metabolic Channeling from the Insulin Receptor to a Novel Class II Phosphatidylinositol 3’-Kinase and Then to the Threonine-308 Site on AKT Drives Overactive de Novo Lipogenesis in the Obese Liver
Patients with the atherometabolic syndrome develop fatty liver and dysglycemia. Both arise from pathway-selective insulin resistance and responsiveness (SEIRR): insulin still drives hepatic de-novo lipogenesis, but controls glucose poorly. We reported that injection of insulin into obese db/db mice fails to inactivate hepatic PTEN, a crucial action of NOX4. Insulin-stimulated db/db livers produce an unusual monophosphorylated form of AKT at Thr308 (pT308-AKT) with only weak phosphorylation at Ser473. Importantly, pT308-AKT activates downstream lipogenic pathways, but fails to phosphorylate FOXO1 or regulate glucose handling. All of these features are recapitulated in cultured hepatocytes by disrupting NOX4.
Any signal from insulin to AKT in the presence of active PTEN is a surprise. Canonically, insulin activates class I PI3 kinases to generate PtdIns(3,4,5)P3. This lipid binds pleckstrin homology (PH) domains in AKT and in the two enzymes that phosphorylate AKT (PDPK1 at Thr308 and mTORC2 at Ser473). Persistent PTEN consumes PtdIns(3,4,5)P3, blocking this pathway.
To explain insulin-stimulated generation of pT308-AKT, we hypothesized a role for the liver-specific class II PI3K, PI3K-C2γ. Insulin stimulates PI3K-C2γ to generate PtdIns(3,4)P2, a lipid that binds PH domains but is a poor substrate for destruction by PTEN. Knock-down of PI3K-C2γ in NOX4-deficient hepatocytes blocked insulin-stimulated formation of pT308-AKT and activation of downstream lipogenic targets.
Here, we explored why PI3K-C2γ activates phosphorylation of AKT at Thr308 over Ser473, even though PDPK1 and mTORC2 both have PH domains. Co-immunoprecipitations revealed a striking difference: PI3K-C2γ robustly associates with PDPK1, but not with SIN1, the component of mTORC2 that contains the PH domain.
Our results demonstrate a parallel, noncanonical signaling pathway in hepatocytes, in which the insulin receptor activates PI3K-C2γ, to generate PtdIns(3,4)P2. Because PI3K-C2γ closely associates with PDPK1, not mTORC2, it selectively triggers AKT phosphorylation at Thr308, not Ser473. The result is SEIRR: continued stimulation of hepatic lipogenesis, but a failure of glucose control. This is the clinical picture of the atherometabolic syndrome.
Author Disclosures: X. Wu: None. K. Williams: Ownership Interest; Significant; Hygieia, Inc..
- © 2014 by American Heart Association, Inc.