Metabolic functions of atypical protein kinase C: "good" and "bad" as defined by nutritional status

Abstract

Atypical protein kinase C (aPKC) isoforms mediate insulin effects on glucose transport in muscle and adipose tissues and lipid synthesis in liver and support other metabolic processes, expression of enzymes needed for islet insulin secretion and hepatic glucose production/release, CNS appetite suppression, and inflammatory responses. In muscle, selective aPKC deficiency impairs glucose uptake and produces insulin resistance and hyperinsulinemia, which, by activating hepatic aPKC, provokes inordinate increases in lipid synthesis and produces typical "metabolic syndrome" features. In contrast, hepatic aPKC deficiency diminishes lipid synthesis and protects against metabolic syndrome features. Unfortunately, aPKC is deficient in muscle but paradoxically conserved in liver in obesity and type 2 diabetes mellitus; this combination is particularly problematic because it promotes lipid and carbohydrate abnormalities. Accordingly, metabolic effects of aPKCs can be "good" or "bad," depending upon nutritional status; thus, muscle glucose uptake, islet insulin secretion, hepatic glucose and lipid production/release, and adipose fat synthesis/storage would be important for survival during periods of limited food availability and therefore be "good." However, during times of food surfeit, excessive activation of hepatic aPKC, whether caused by overnutrition or impairments in extrahepatic effects of insulin, would lead to inordinate increases in hepatic lipid synthesis and metabolic syndrome features and therefore be "bad." In keeping with these ideas, the inhibition of hepatic aPKC markedly ameliorates lipid and carbohydrate abnormalities in experimental models of obesity and type 2 diabetes. We postulate that a similar approach may be useful for treating humans.

Fig. 1.

Activation of atypical PKC (aPKC) by insulin and AMP-activated protein kinase (AMPK) activators. Increases in acidic phospholipids, phosphatidylinositol-(PO₄)₃ (PIP₃) via phosphatidylinositol 3-kinase (PI3K) action, and phosphatidic acid (PA) via phospholipase D (PLD) action presumably bind to basic arginine residues in or near the pseudosubstrate site (PS) in the regulatory domain and thereby open the major cleft and facilitate phosphoinositide-dependent kinase-1 (PDK1) access to the activation loop (or T-loop site), subsequent autophosphorylation and substrate access to the catalytic site. 5-aminoimidazole-4-carboxamide-1-β-d-riboside (AICAR) is converted to 5-aminoimidazole-4-carboxamide-1-β-d-ribosyl monophosphate (ZMP) and analog of 5′-AMP, and metformin, like AICAR, activates AMPK, perhaps by increasing the AMP/ATP ratio or via LKB. Factors that couple AMPK to ERK (X1) and ERK to PLD (X2) are uncertain, but Ca⁺⁺-dependent proline-rich tyrosine kinase 2 (PYK2) may be involved. IRS-1/2, insulin receptor substrate-1 and -2.