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

Abstract

tein 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, aPKC, -, and -, are members of the phospholipid/lipid-regulated PKC family that are activated by acidic phospholipids, phosphatidylinositol-1,3,5-(PO 4 ) 3 (PIP 3 ), and phosphatidic acid (PA) rather than by the neutral lipid, diacylglycerol (DAG), and Ca ϩϩ , which activate "typical" PKCs. However, it is a misnomer to consider aPKCs as "atypical" relative to typical DAG-dependent/Ca ϩϩ -dependent classical/conventional PKCs (cPKCs␣, -␤, and -␥) and DAG-dependent/Ca ϩϩ -independent novel PKCs (nPKC␦, -ε, -, and -). 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-B via aPKC-dependent phosphorylation of both IKK␣/␤ (24), a kinase that phosphorylates the inhibitor of B...

Cellular depletion of atypical PKCλ is associated with enhanced insulin sensitivity and glucose uptake in L6 rat skeletal muscle cells

“…However, notwithstanding this difference in aPKC isoform expression, our studies reveal that a substantial depletion of PKC results in enhanced insulin sensitivity as judged using PKB activation and insulin-stimulated glucose uptake as readouts. This finding runs counter to the suggestion [see review and references cited therein (14)] that aPKCs are indispensible components of the mechanism underpinning the insulindependent stimulation of glucose uptake, at least in the cell model used in the current studies. In contrast, the observed increase in insulin sensitivity of PKC-depleted cells is consistent with the view that aPKCs may normally function to restrain IRS-1 and PKB-directed signaling.…”

“…14 for a review). Based on expression of dominant interfering aPKC isoforms and use of nonselective PKC inhibitors, it has been suggested that activation of aPKCs in response to insulin is essential for promoting GLUT4 translocation to the cell surface and for supporting the associated increase in glucose uptake (14). However, somewhat paradoxically, activation of aPKCs by proinflammatory stimuli such as tumor necrosis factor-␣ (24), saturated fatty acids, and fatty acid-derived lipids such as ceramide (8,29) is associated with marked suppression of both insulin signaling and glucose transport (27,29).…”

Anthocyanin inhibits high glucose-induced hepatic mtGPAT1 activation and prevents fatty acid synthesis through PKCζ

“…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 ( 41 ). Hepatic aPKC-dependent activation of sterol regulatory binding protein-1c and nuclear factor-B contributes to the development of hepatic lipogenesis, hyperlipidemia, and systemic insulin resistance.…”

Mechanisms for greater insulin-stimulated glucose uptake in normal and insulin-resistant skeletal muscle after acute exercise

“…Frøsig et al (35) reported that acute one-legged exercise by men did not alter subsequent (4 h postexercise) insulinstimulated atypical PKC (aPKC) activity without exogenous phosphatidylinositol-3,4,5-trisphosphate (PIP3), but aPKC activity measured with exogenous PIP3 was greater for the exercised vs. unexercised leg. Conflicting results implicate aPKC as being positively related, negatively related, or unrelated to insulin-stimulated glucose uptake (28,29,109,120). Frøsig et al (35) also reported greater IRS-2/PI3K for the exercised vs. unexercised leg, but IRS-1 appears to be more important than IRS-2 for insulin-stimulated muscle glucose uptake (7,53,115).…”