Role of Atypical Protein Kinase C in Activation of Sterol Regulatory Element Binding Protein-1c and Nuclear Factor Kappa B (NFkappaB) in Liver of Rodents Used As a Model of Diabetes, and Relationships to Hyperlipidaemia and Insulin Resistance

Overview

Journal Diabetologia

Specialty Endocrinology

Date 2009 Apr 10

PMID 19357831

Citations 29

Authors

M P Sajan

M L Standaert

J Rivas

A Miura

Y Kanoh

J Soto

C M Taniguchi

C R Kahn

R V Farese

Affiliations

Soon will be listed here.

Abstract

Aims/hypothesis: Previous findings in rodents used as a model of diabetes suggest that insulin activation of atypical protein kinase C (aPKC) is impaired in muscle, but, unexpectedly, conserved in liver, despite impaired hepatic protein kinase B (PKB/Akt) activation. Moreover, aPKC at least partly regulates two major transactivators: (1) hepatic sterol receptor binding protein-1c (SREBP-1c), which controls lipid synthesis; and (2) nuclear factor kappa B (NFkappaB), which promotes inflammation and systemic insulin resistance.

Methods: In Goto-Kakizaki rats used as a model of type 2 diabetes, we examined: (1) whether differences in hepatic aPKC and PKB activation reflect differences in activation of IRS-1- and IRS-2-dependent phosphatidylinositol 3-kinase (PI3K); (2) whether hepatic SREBP-1c and NFkappaB are excessively activated by aPKC; and (3) metabolic consequences of excessive activation of hepatic aPKC, SREBP-1c and NFkappaB.

Results: In liver, as well as in muscle, IRS-2/PI3K activation by insulin was intact, whereas IRS-1/PI3K activation by insulin was impaired. Moreover, hepatic IRS-2 is known to control hepatic aPKC during insulin activation. Against this background, selective inhibition of hepatic aPKC by adenoviral-mediated expression of mRNA encoding kinase-inactive aPKC or short hairpin RNA targeting Irs2 mRNA and partially depleting hepatic IRS-2 diminished hepatic SREBP-1c production and NFkappaB activities, concomitantly improving serum lipids and insulin signalling in muscle and liver. Similar improvements in SREBP-1c, NFkappaB and insulin signalling were seen in ob/ob mice following inhibition of hepatic aPKC.

Conclusions/interpretation: In diabetic rodent liver, diminished PKB activation may largely reflect impaired IRS-1/PI3K activation, while conserved aPKC activation reflects retained IRS-2/PI3K activity. Hepatic aPKC may also contribute importantly to excessive SREPB-1c and NFkappaB activities. Excessive hepatic aPKC-dependent activation of SREBP-1c and NFkappaB may contribute importantly to hyperlipidaemia and systemic insulin resistance.

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References

Cai D, Yuan M, Frantz D, Melendez P, Hansen L, Lee J . Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med. 2005; 11(2):183-90. PMC: 1440292. DOI: 10.1038/nm1166. View

Taniguchi C, Ueki K, Kahn R . Complementary roles of IRS-1 and IRS-2 in the hepatic regulation of metabolism. J Clin Invest. 2005; 115(3):718-27. PMC: 548317. DOI: 10.1172/JCI23187. View

Kerouz N, Horsch D, Pons S, Kahn C . Differential regulation of insulin receptor substrates-1 and -2 (IRS-1 and IRS-2) and phosphatidylinositol 3-kinase isoforms in liver and muscle of the obese diabetic (ob/ob) mouse. J Clin Invest. 1998; 100(12):3164-72. PMC: 508530. DOI: 10.1172/JCI119872. View

Shimomura I, Matsuda M, Hammer R, Bashmakov Y, Brown M, Goldstein J . Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice. Mol Cell. 2000; 6(1):77-86. View

Krook A, Kawano Y, Song X, Efendic S, Roth R, Wallberg-Henriksson H . Improved glucose tolerance restores insulin-stimulated Akt kinase activity and glucose transport in skeletal muscle from diabetic Goto-Kakizaki rats. Diabetes. 1997; 46(12):2110-4. DOI: 10.2337/diab.46.12.2110. View

Kanoh Y, Bandyopadhyay G, Sajan M, Standaert M, Farese R . Rosiglitazone, insulin treatment, and fasting correct defective activation of protein kinase C-zeta/lambda by insulin in vastus lateralis muscles and adipocytes of diabetic rats. Endocrinology. 2001; 142(4):1595-605. DOI: 10.1210/endo.142.4.8066. View

Matsumoto M, Ogawa W, Akimoto K, Inoue H, Miyake K, Furukawa K . PKClambda in liver mediates insulin-induced SREBP-1c expression and determines both hepatic lipid content and overall insulin sensitivity. J Clin Invest. 2003; 112(6):935-44. PMC: 193669. DOI: 10.1172/JCI18816. View

Duran A, Diaz-Meco M, Moscat J . Essential role of RelA Ser311 phosphorylation by zetaPKC in NF-kappaB transcriptional activation. EMBO J. 2003; 22(15):3910-8. PMC: 169043. DOI: 10.1093/emboj/cdg370. View

Zhang W, Patil S, Chauhan B, Guo S, Powell D, Le J . FoxO1 regulates multiple metabolic pathways in the liver: effects on gluconeogenic, glycolytic, and lipogenic gene expression. J Biol Chem. 2006; 281(15):10105-17. DOI: 10.1074/jbc.M600272200. View

10.

Fleischmann M, Iynedjian P . Regulation of sterol regulatory-element binding protein 1 gene expression in liver: role of insulin and protein kinase B/cAkt. Biochem J. 2000; 349(Pt 1):13-7. PMC: 1221114. DOI: 10.1042/0264-6021:3490013. View

11.

Shoelson S, Herrero L, Naaz A . Obesity, inflammation, and insulin resistance. Gastroenterology. 2007; 132(6):2169-80. DOI: 10.1053/j.gastro.2007.03.059. View

12.

Standaert M, Sajan M, Miura A, Kanoh Y, Chen H, Farese Jr R . Insulin-induced activation of atypical protein kinase C, but not protein kinase B, is maintained in diabetic (ob/ob and Goto-Kakazaki) liver. Contrasting insulin signaling patterns in liver versus muscle define phenotypes of type 2 diabetic and high.... J Biol Chem. 2004; 279(24):24929-34. DOI: 10.1074/jbc.M402440200. View

13.

Sajan M, Rivas J, Li P, Standaert M, Farese R . Repletion of atypical protein kinase C following RNA interference-mediated depletion restores insulin-stimulated glucose transport. J Biol Chem. 2006; 281(25):17466-17473. DOI: 10.1074/jbc.M510803200. View

14.

Hashimoto N, Kido Y, Uchida T, Matsuda T, Suzuki K, Inoue H . PKClambda regulates glucose-induced insulin secretion through modulation of gene expression in pancreatic beta cells. J Clin Invest. 2005; 115(1):138-45. PMC: 539193. DOI: 10.1172/JCI22232. View

15.

Valverde A, Burks D, Fabregat I, Fisher T, Carretero J, White M . Molecular mechanisms of insulin resistance in IRS-2-deficient hepatocytes. Diabetes. 2003; 52(9):2239-48. DOI: 10.2337/diabetes.52.9.2239. View

16.

Taniguchi C, Kondo T, Sajan M, Luo J, Bronson R, Asano T . Divergent regulation of hepatic glucose and lipid metabolism by phosphoinositide 3-kinase via Akt and PKClambda/zeta. Cell Metab. 2006; 3(5):343-53. DOI: 10.1016/j.cmet.2006.04.005. View

17.

Farese R, Sajan M, Yang H, Li P, Mastorides S, Gower Jr W . Muscle-specific knockout of PKC-lambda impairs glucose transport and induces metabolic and diabetic syndromes. J Clin Invest. 2007; 117(8):2289-301. PMC: 1913489. DOI: 10.1172/JCI31408. View

18.

Brown M, Goldstein J . Selective versus total insulin resistance: a pathogenic paradox. Cell Metab. 2008; 7(2):95-6. DOI: 10.1016/j.cmet.2007.12.009. View

19.

Shimomura I, Bashmakov Y, Ikemoto S, Horton J, Brown M, Goldstein J . Insulin selectively increases SREBP-1c mRNA in the livers of rats with streptozotocin-induced diabetes. Proc Natl Acad Sci U S A. 1999; 96(24):13656-61. PMC: 24120. DOI: 10.1073/pnas.96.24.13656. View

20.

Sajan M, Standaert M, Miura A, Kahn C, Farese R . 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. Mol Endocrinol. 2004; 18(10):2513-21. DOI: 10.1210/me.2004-0045. View