Class III PI3K regulates organismal glucose homeostasis by providing negative feedback on hepatic insulin signalling

Abstract

Defective hepatic insulin receptor (IR) signalling is a pathogenic manifestation of metabolic disorders including obesity and diabetes. The endo/lysosomal trafficking system may coordinate insulin action and nutrient homeostasis by endocytosis of IR and the autophagic control of intracellular nutrient levels. Here, we show that class III PI3K - a master regulator of endocytosis, endosomal sorting and autophagy - provides negative feedback on hepatic insulin signalling. The Ultraviolet radiation resistance associated gene protein (UVRAG) associated-class III PI3K complex interacts with IR and is stimulated by insulin treatment. Acute and chronic depletion of hepatic Vps15, the regulatory subunit of class III PI3K, increases insulin sensitivity and Akt signalling, an effect that requires functional IR. This is reflected by FoxO1-dependent transcriptional defects and blunted gluconeogenesis in Vps15 mutant cells. Upon depletion of Vps15, the metabolic syndrome in genetic and diet-induced models of insulin resistance and diabetes is alleviated. Thus, feedback regulation of IR trafficking and function by class III PI3K may be a therapeutic target in metabolic conditions of insulin resistance.

Growth factor receptor binding protein 14 inhibition triggers insulin‐induced mouse hepatocyte proliferation and is associated with hepatocellular carcinoma

“…IR‐B thus remained the major isoform expressed in Grb14i liver (http://onlinelibrary.wiley.com/doi/10.1002/hep.28972/suppinfo). To investigate whether the proliferative effect observed after liver Grb14 inhibition was attributable to IR activation or to other Grb14 partners, we used an iLIRKO mouse line (Fig. A).…”

“…Nine‐week‐old male mice were purchased from Harlan Laboratories (C57BL6/J) and adapted to the environment for 1 week before study. The inducible liver IR knockout (iLIRKO) mice have been described . Fifteen‐week‐old male mice were studied 3 weeks after IR deletion.…”

“…The inducible liver IR knockout (iLIRKO) mice have been described. (20) Fifteen-week-old male mice were studied 3 weeks after IR deletion. Generation of S6K1 -/-/ S6K2 -/mice (S6K DKO) has been described.…”

Role of phosphatidylinositol-4,5-bisphosphate 3-kinase signaling in vesicular trafficking

“…Liver hepatocytes demonstrate regulation of class III PI3K via insulin stimulation that functions to modulate insulin receptor (IR) trafficking and its lysosomal degradation. Downregulation of Vsp15, a regulatory subunit of class III PI3K, leads to compromised internalization and degradation of IR and affects overall trafficking 66 . This study emphasizes that PI3K is a critical player in regulation of vesicle trafficking and a potential target for the treatment of metabolic conditions involving aberrant insulin signaling.…”

Beclin 1-Vps34 complex architecture: Understanding the nuts and bolts of therapeutic targets

“…In contrast, the negative autophagy regulator Rubicon binds UVRAG when S498 of UVRAG is phosphorylated by mTORC1, inhibiting autophagosome maturation [21,22,80]. Despite consensus on the role of UVRAG in endosomal trafficking and autophagosome maturation, as well as the recent exciting findings of autolysosome tubule scission [81], insulin sensing and organismal glucose homeostasis regulation [82] by the UVRAG-containing Beclin 1-Vps34 complex, it remains under debate whether the UVRAG-containing Beclin 1-Vps34 complex plays a role in autophagosome formation. For example, some evidence shows that UVRAG associates with Bif-1 and Beclin 1 to promote autophagosome formation [23,83]; conversely, other groups were unable to detect autophagy impairment upon UVRAG deficiency [73,84].…”