Metabolic Functions of Atypical Protein Kinase C: “good” and “bad” as Defined by Nutritional Status

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. atypical protein kinase c (aPKC) isoforms, aPKCι, -λ, and -ζ, are members of the phospholipid/lipid-regulated PKC family that are activated by acidic phospholipids, phosphatidylinositol-1,3,5-(PO4)3 (PIP3), and phosphatidic acid (PA) rather than by the neutral lipid, diacylglycerol (DAG), and Ca++, which activate “typical” PKCs. However, it is a misnomer to consider aPKCs as “atypical” relative to typical DAG-dependent/Ca++-dependent classical/conventional PKCs (cPKCsα, -β, and -γ) and DAG-dependent/Ca++-independent novel PKCs (nPKCδ, -ε, -η, and -θ). This nomenclature reflects the historical order of discovery of cPKCs, nPKCs, and aPKCs rather than their biological importance. Indeed, aPKCs are archetypal protein kinases that have widespread occurrence throughout plant and animal kingdoms and are indispensable in a wide variety of essential cellular functions independent of typical PKCs. aPKCs participate importantly in regulating multiple cellular processes pertinent to this review, including 1) determination of cellular polarity and related functions, i.e., motility, adhesion, differentiation, and embryogenesis; 2) activation of the immune response transactivator NF-κB via aPKC-dependent phosphorylation of both IKKα/β (24), a kinase that phosphorylates the inhibitor of κB (IκB), a tonic binder and inhibitor of NFκB, thereby releasing and targeting IκB for ubiquitinylation-mediated destruction and thereby freeing NF-κB to translocate from cytosol to nucleus, and Thr311 in the RelA subunit of NF-κB, which regulates the transcription of an array of genes involved in production of cytokines that not only mediate inflammatory/immune responses (14) but can also increase systemic insulin resistance (12); 3) signaling by various growth factors, including IGF-I and insulin, that act through phosphatidylinositol 3-kinase (PI3K) to activate both aPKC and Akt/PKB (5) and thereby control various metabolic processes, including glucose transport in myocytes and adipocytes by increasing GLUT4 glucose transporter translocation to the plasma membrane (5, 15, 23, 38), and lipogenesis in liver by increased expression/activation of sterol receptor element-binding protein-1c (SREBP-1c), which transactivates multiple lipogenic enzymes (30, 53); 4) cell growth by activation of ERK1/2 and other MAPKs (39, 20) and/or cyclin-dependent kinase-activating kinase (9); 5) protein synthesis by activation of p70 S6 kinase (35); 6) regulation of genes required for critical pancreatic islet β-cell functions, including insulin production and release (19); and 7) signaling downstream of other signaling factors, e.g., Src kinase (20), phospholipase D (PLD) (17, 13), proline-rich tyrosine kinase 2 (13), and AMP-activated kinase (AMPK) (13). The ability of aPKCs to bind Par6 and other key scaffolding molecules in signaling complexes and the movement of activated aPKCs to the plasma membrane and nuclear sites undoubtedly are important events in explaining the pleiotropic effects of aPKCs. Here, we will focus on the role of aPKCs in metabolic processes, most notably insulin actions on carbohydrate and lipid metabolism and insulin secretion, in both health and disease states of obesity and diabetes mellitus. As this review unfolds (see Table 1), it will become apparent that aPKCs are likely to have served in metabolic processes essential for survival during periods of limited food intake but unfortunately have detrimental effects when activated more persistently during periods of dietary excess