title: Atypical protein kinase C in cardiometabolic abnormalities.
abstract: OBJECTIVE
  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).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Medical and Research Services, James A. Haley Veterans Medical Center Department of Internal Medicine, University of South Florida College of Medicine, Tampa Metabolism Division, Roskamp Institute, Sarasota, Florida, USA.
authors.forename: Robert V
authors.initials: RV
authors.lastname: Farese
authors.forename: Mini P
authors.initials: MP
authors.lastname: Sajan
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases / Q000150:complications / Q000188:drug therapy / Q000201:enzymology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008659:Metabolic Diseases / Q000150:complications / Q000188:drug therapy / Q000201:enzymology*; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use; D009206:Myocardium / Q000201:enzymology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D007328:Insulin; D008687:Metformin; D011493:Protein Kinase C