title: Higher protein kinase C ζ in fatty rat liver and its effect on insulin actions in primary hepatocytes.
abstract: We previously showed the impairment of insulin-regulated gene expression in the primary hepatocytes from Zucker fatty (ZF) rats, and its association with alterations of hepatic glucose and lipid metabolism. However, the molecular mechanism is unknown. A preliminary experiment shows that the expression level of protein kinase C ζ (PKCζ), a member of atypical PKC family, is higher in the liver and hepatocytes of ZF rats than that of Zucker lean (ZL) rats. Herein, we intend to investigate the roles of atypical protein kinase C in the regulation of hepatic gene expression. The insulin-regulated hepatic gene expression was evaluated in ZL primary hepatocytes treated with atypical PKC recombinant adenoviruses. Recombinant adenovirus-mediated overexpression of PKCζ, or the other atypical PKC member PKCι/λ, alters the basal and impairs the insulin-regulated expressions of glucokinase, sterol regulatory element-binding protein 1c, the cytosolic form of phosphoenolpyruvate carboxykinase, the catalytic subunit of glucose 6-phosphatase, and insulin like growth factor-binding protein 1 in ZL primary hepatocytes. PKCζ or PKCι/λ overexpression also reduces the protein level of insulin receptor substrate 1, and the insulin-induced phosphorylation of AKT at Ser473 and Thr308. Additionally, PKCι/λ overexpression impairs the insulin-induced Prckz expression, indicating the crosstalk between PKCζ and PKCι/λ. We conclude that the PKCζ expression is elevated in hepatocytes of insulin resistant ZF rats. Overexpressions of aPKCs in primary hepatocytes impair insulin signal transduction, and in turn, the down-stream insulin-regulated gene expression. These data suggest that elevation of aPKC expression may contribute to the hepatic insulin resistance at gene expression level.
authors.affiliation: Department of Nutrition, University of Tennessee at Knoxville, Knoxville, Tennessee, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Nutrition, University of Tennessee at Knoxville, Knoxville, Tennessee, United States of America.
authors.forename: Matthew Ray
authors.initials: MR
authors.lastname: Goff
authors.affiliation: Department of Nutrition, University of Tennessee at Knoxville, Knoxville, Tennessee, United States of America.
authors.forename: Heqian
authors.initials: H
authors.lastname: Kuang
authors.affiliation: Department of Nutrition, University of Tennessee at Knoxville, Knoxville, Tennessee, United States of America.
authors.forename: Guoxun
authors.initials: G
authors.lastname: Chen
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D015398:Signal Transduction; D015854:Up-Regulation; D000099293:Protein Kinase C-lambda; D000099221:Protein Kinase C zeta
chemical_list: D007328:Insulin; D007527:Isoenzymes; D011493:Protein Kinase C; D012333:RNA, Messenger; D000099293:Protein Kinase C-lambda; D000099221:Protein Kinase C zeta
references.citation: J Biol Chem. 2004 Jun 11;279(24):24929-34
references.pmid: 15069067
references.citation: Biochem J. 2003 Dec 15;376(Pt 3):697-705
references.pmid: 14505487
references.citation: J Nutr Biochem. 2014 Sep;25(9):964-76
references.pmid: 24973045
references.citation: Diabetes. 2014 Aug;63(8):2690-701
references.pmid: 24705403
references.citation: Am J Physiol Endocrinol Metab. 2010 Mar;298(3):E385-94
references.pmid: 19996389
references.citation: EMBO J. 1996 Dec 2;15(23):6541-51
references.pmid: 8978681
references.citation: Mol Endocrinol. 2004 Oct;18(10):2513-21
references.pmid: 15256535
references.citation: Science. 2003 Dec 5;302(5651):1710-1
references.pmid: 14657487
references.citation: J Biol Chem. 2009 Oct 2;284(40):27031-5
references.pmid: 19636079
references.citation: J Biol Chem. 2004 Jan 23;279(4):2623-31
references.pmid: 14612449
references.citation: Am J Physiol Endocrinol Metab. 2003 Oct;285(4):E685-92
references.pmid: 12959935
references.citation: Cell Mol Life Sci. 2009 Jan;66(1):27-42
references.pmid: 18726182
references.citation: J Biol Chem. 2001 Feb 2;276(5):3543-9
references.pmid: 11063744
references.citation: Nat Rev Mol Cell Biol. 2010 Jan;11(1):9-22
references.pmid: 20027184
references.citation: Endocrinology. 1972 May;90(5):1320-30
references.pmid: 5012744
references.citation: PLoS One. 2014 Aug 08;9(8):e100868
references.pmid: 25105869
references.citation: Physiol Rev. 1996 Oct;76(4):1109-61
references.pmid: 8874496
references.citation: Diabetologia. 2013 Nov;56(11):2507-16
references.pmid: 23933835
references.citation: Diabetologia. 2009 Jun;52(6):1197-207
references.pmid: 19357831
references.citation: J Biol Chem. 2009 May 29;284(22):15071-83
references.pmid: 19366697
references.citation: J Biol Chem. 2001 Apr 27;276(17):14459-65
references.pmid: 11278339
references.citation: PLoS One. 2011;6(6):e21342
references.pmid: 21731709
references.citation: Biochem J. 2000 Nov 1;351 Pt 3:621-7
references.pmid: 11042116
references.citation: Proc Natl Acad Sci U S A. 2012 Oct 2;109(40):16184-9
references.pmid: 22927400
references.citation: Proc Natl Acad Sci U S A. 2004 Aug 3;101(31):11245-50
references.pmid: 15266058
references.citation: Nat Med. 2004 Jun;10(6):633-7
references.pmid: 15146178
references.citation: Cell Metab. 2007 Sep;6(3):208-16
references.pmid: 17767907
references.citation: J Lipid Res. 2009 Jun;50(6):1133-45
references.pmid: 19202134
references.citation: J Biol Chem. 2008 Nov 21;283(47):32432-41
references.pmid: 18805788
references.citation: J Clin Invest. 2003 Sep;112(6):935-44
references.pmid: 12975478
references.citation: Nature. 2003 May 29;423(6939):550-5
references.pmid: 12754525
references.citation: PLoS One. 2012;7(9):e45210
references.pmid: 23028851
references.citation: J Biol Chem. 2004 Jun 11;279(24):25157-63
references.pmid: 15069075
references.citation: Cell Metab. 2006 May;3(5):343-53
references.pmid: 16679292
references.citation: Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3441-6
references.pmid: 20133650
references.citation: J Clin Invest. 2002 May;109(9):1125-31
references.pmid: 11994399
references.citation: Diabetologia. 2012 May;55(5):1446-57
references.pmid: 22349071
references.citation: Cell. 2009 May 15;137(4):635-46
references.pmid: 19450513
references.citation: Am J Physiol Endocrinol Metab. 2009 Oct;297(4):E898-906
references.pmid: 19638508
references.citation: Metabolism. 2012 Apr;61(4):459-69
references.pmid: 22225955
references.citation: Curr Opin Lipidol. 2012 Jun;23(3):175-181
references.pmid: 22449812
references.citation: Biochem J. 2000 Jul 1;349(Pt 1):13-7
references.pmid: 10861205
references.citation: Prog Mol Biol Transl Sci. 2014;121:165-215
references.pmid: 24373238