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Review
. 2012 Jun;23(3):175-181.
doi: 10.1097/MOL.0b013e328352c4c7.

Atypical protein kinase C in cardiometabolic abnormalities

Robert V Farese  1 , Mini P Sajan
Affiliations
Review

Atypical protein kinase C in cardiometabolic abnormalities

Robert V Farese et al. Curr Opin Lipidol. 2012 Jun.

Abstract

Purpose of review: To review the aberrations of insulin signaling to atypical protein kinase C (aPKC) in muscle and liver that generate cardiovascular risk factors, including obesity, hypertriglyceridemia, hypercholesterolemia, insulin resistance and glucose intolerance in type 2 diabetes mellitus (T2DM), and obesity-associated metabolic syndrome (MetSyn).

Recent findings: aPKC and Akt mediate the insulin effects on glucose transport in muscle and synthesis of lipids, cytokines and glucose in liver. In T2DM, whereas Akt and aPKC activation are diminished in muscle, and hepatic Akt activation is diminished, hepatic aPKC activation is conserved. Imbalance between muscle and hepatic aPKC activation (and expression of PKC-ι in humans) by insulin results from differential downregulation of insulin receptor substrates that control phosphatidylinositol-3-kinase. Conserved activation of hepatic aPKC in hyperinsulinemic states of T2DM, obesity and MetSyn is problematic, as excessive activation of aPKC-dependent lipogenic, gluconeogenic and proinflammatory pathways increases the cardiovascular risk factors. Indeed, selective inhibition of hepatic aPKC by adenoviral-mediated expression of kinase-inactive aPKC, or newly developed small-molecule biochemicals, dramatically improves abdominal obesity, hepatosteatosis, hypertriglyceridemia, hypercholesterolemia, insulin resistance and glucose intolerance in murine models of obesity and T2DM.

Summary: Hepatic aPKC is a unifying target for treating multiple clinical abnormalities that increase the cardiovascular risk in insulin-resistant states of obesity, MetSyn and T2DM.

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References

    1. Farese RV, Sajan MP. Metabolic Functions of Atypical Protein Kinase C: “Good and Bad” as Defined by Nutritional Status. (Invited Review) Am J Physiol Endocrinol Metab. 2010;298:E385–394. This reviews mechanisms of aPKC activation and the role of aPKC, along with that of Akt, in metabolic effects of insulin. It suggests that aPKC served as a necessary survival gene in periods of limited food access, but became a liability during periods of food surfeit, chiefly because of hyperinsulinemia-driven overactivity in liver and subsequent increases in hepatic lipid production. - PMC - PubMed
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    1. Sajan MP, Standaert ML, Miura A, Farese RV. Tissue-specific differences in activation of atypical protein kinase C and protein kinase B in muscle, liver and adipocytes of insulin receptor substrate-1 knockout mice. Molecular Endocrinology. 2004;18:2513–2521. - PubMed
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