Correction of metabolic abnormalities in a rodent model of obesity, metabolic syndrome, and type 2 diabetes mellitus by inhibitors of hepatic protein kinase C-ι

Mini P. Sajan, Sonali Nimal, Stephen Mastorides, Mildred Acevedo-Duncan, C. Ronald Kahn, Alan P Fields, Ursula Braun, Michael Leitges, Robert V. Farese

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Abstract

Excessive activity of hepatic atypical protein kinase (aPKC) is proposed to play a critical role in mediating lipid and carbohydrate abnormalities in obesity, the metabolic syndrome, and type 2 diabetes mellitus. In previous studies of rodent models of obesity and type 2 diabetes mellitus, adenoviral-mediated expression of kinase-inactive aPKC rapidly reversed or markedly improved most if not all metabolic abnormalities. Here, we examined effects of 2 newly developed small-molecule PKC-ι/λ inhibitors. We used the mouse model of heterozygous muscle-specific knockout of PKC-λ, in which partial deficiency of muscle PKC-λ impairs glucose transport in muscle and thereby causes glucose intolerance and hyperinsulinemia, which, via hepatic aPKC activation, leads to abdominal obesity, hepatosteatosis, hypertriglyceridemia, and hypercholesterolemia. One inhibitor, 1H-imidazole-4-carboxamide, 5-amino-1-[2,3-dihydroxy-4-[(phosphonooxy)methyl] cyclopentyl-[1R-(1a,2b,3b,4a)], binds to the substrate-binding site of PKC-λ/ι, but not other PKCs. The other inhibitor, aurothiomalate, binds to cysteine residues in the PB1-binding domains of aPKC-λ/ι/ ζ and inhibits scaffolding. Treatment with either inhibitor for 7 days inhibited aPKC, but not Akt, in liver and concomitantly improved insulin signaling to Akt and aPKC in muscle and adipocytes. Moreover, both inhibitors diminished excessive expression of hepatic, aPKC-dependent lipogenic, proinflammatory, and gluconeogenic factors; and this was accompanied by reversal or marked improvements in hyperglycemia, hyperinsulinemia, abdominal obesity, hepatosteatosis, hypertriglyceridemia, and hypercholesterolemia. Our findings highlight the pathogenetic importance of insulin signaling to hepatic PKC-ι in obesity, the metabolic syndrome, and type 2 diabetes mellitus and suggest that 1H-imidazole-4-carboxamide, 5-amino-1-[2,3-dihydroxy-4-[(phosphonooxy) methyl]cyclopentyl-[1R-(1a,2b,3b,4a)] and aurothiomalate or similar agents that selectively inhibit hepatic aPKC may be useful treatments.

Original languageEnglish (US)
Pages (from-to)459-469
Number of pages11
JournalMetabolism: Clinical and Experimental
Volume61
Issue number4
DOIs
StatePublished - Apr 2012

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Type 2 Diabetes Mellitus
Protein Kinase C
Rodentia
Obesity
Liver
Aminoimidazole Carboxamide
Gold Sodium Thiomalate
Muscles
Abdominal Obesity
Hypertriglyceridemia
Hyperinsulinism
Hypercholesterolemia
Insulin
Glucose Intolerance
Adipocytes
Hyperglycemia
Protein Kinases
Cysteine
Phosphotransferases
Binding Sites

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Correction of metabolic abnormalities in a rodent model of obesity, metabolic syndrome, and type 2 diabetes mellitus by inhibitors of hepatic protein kinase C-ι. / Sajan, Mini P.; Nimal, Sonali; Mastorides, Stephen; Acevedo-Duncan, Mildred; Kahn, C. Ronald; Fields, Alan P; Braun, Ursula; Leitges, Michael; Farese, Robert V.

In: Metabolism: Clinical and Experimental, Vol. 61, No. 4, 04.2012, p. 459-469.

Research output: Contribution to journalArticle

Sajan, Mini P. ; Nimal, Sonali ; Mastorides, Stephen ; Acevedo-Duncan, Mildred ; Kahn, C. Ronald ; Fields, Alan P ; Braun, Ursula ; Leitges, Michael ; Farese, Robert V. / Correction of metabolic abnormalities in a rodent model of obesity, metabolic syndrome, and type 2 diabetes mellitus by inhibitors of hepatic protein kinase C-ι. In: Metabolism: Clinical and Experimental. 2012 ; Vol. 61, No. 4. pp. 459-469.
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