title: Palmitate-induced down-regulation of sortilin and impaired GLUT4 trafficking in C2C12 myotubes.
abstract: Elevated saturated FFAs including palmitate (C16:0) are a primary trigger for peripheral insulin resistance characterized by impaired glucose uptake/disposal in skeletal muscle, resulting from impaired GLUT4 translocation in response to insulin. We herein demonstrate that palmitate induces down-regulation of sortilin, a sorting receptor implicated in the formation of insulin-responsive GLUT4 vesicles, via mechanisms involving PKC and TNF-α-converting enzyme, but not p38, JNK, or mitochondrial reactive oxygen species generation, leading to impaired GLUT4 trafficking in C2C12 myotubes. Intriguingly, unsaturated FFAs such as palmitoleate (C16:1) and oleate (C18:1) had no such detrimental effects, appearing instead to effectively reverse palmitate-induced impairment of insulin-responsive GLUT4 recycling along with restoration of sortilin abundance by preventing aberrant PKC activation. On the other hand, shRNA-mediated reduction of sortilin in intact C2C12 myotubes inhibited insulin-induced GLUT4 recycling without dampening Akt phosphorylation. We found that the peroxisome proliferator-activated receptor γ agonist troglitazone prevented the palmitate-induced sortilin reduction and also ameliorated insulin-responsive GLUT4 recycling without altering the palmitate-evoked insults on signaling cascades; neither highly phosphorylated PKC states nor impaired insulin-responsive Akt phosphorylation was affected. Taken together, our data provide novel insights into the pathogenesis of PKC-dependent insulin resistance with respect to insulin-responsive GLUT4 translocation, which could occur not only through defects of insulin signaling but also via a reduction of sortilin, which directly controls trafficking/sorting of GLUT4 in skeletal muscle cells. In addition, our data suggest the insulin-sensitizing action of peroxisome proliferator-activated receptor γ agonists to be at least partially mediated through the restoration of proper GLUT4 trafficking/sorting events governed by sortilin.
authors.affiliation: Graduate School of Biomedical Engineering, Tohoku University, Sendai 980-8575, Japan.
authors.forename: Yo
authors.initials: Y
authors.lastname: Tsuchiya
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Hatakeyama
authors.forename: Natsumi
authors.initials: N
authors.lastname: Emoto
authors.forename: Fumie
authors.initials: F
authors.lastname: Wagatsuma
authors.forename: Shinichi
authors.initials: S
authors.lastname: Matsushita
authors.forename: Makoto
authors.initials: M
authors.lastname: Kanzaki
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000072198:ADAM17 Protein; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002839:Chromans / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D007333:Insulin Resistance; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008931:Mitochondria, Muscle / Q000235:genetics / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D019308:Palmitic Acid / Q000378:metabolism / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D045162:Thiazolidinediones / Q000494:pharmacology; D000077288:Troglitazone; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000099183:Sortilin
chemical_list: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D033942:Adaptor Proteins, Vesicular Transport; D002839:Chromans; D051275:Glucose Transporter Type 4; D007328:Insulin; D048670:MAP Kinase Kinase 4; D047495:PPAR gamma; D019308:Palmitic Acid; D010975:Platelet Aggregation Inhibitors; D011493:Protein Kinase C; D017382:Reactive Oxygen Species; D045162:Thiazolidinediones; D000077288:Troglitazone; D048051:p38 Mitogen-Activated Protein Kinases; D000099183:Sortilin; C495693:Slc2a4 protein, mouse; C081975:protein kinase C eta
references.citation: Am J Physiol Endocrinol Metab. 2009 Dec;297(6):E1291-303
references.pmid: 19755671
references.citation: Endocrinology. 2005 Jul;146(7):3087-95
references.pmid: 15802498
references.citation: Cell Metab. 2008 May;7(5):421-33
references.pmid: 18460333
references.citation: Diabetologia. 2009 May;52(5):932-40
references.pmid: 19219422
references.citation: Int J Obes Relat Metab Disord. 2002 Sep;26 Suppl 2:S39-45
references.pmid: 12174327
references.citation: J Clin Invest. 2004 Sep;114(6):823-7
references.pmid: 15372106
references.citation: Br J Pharmacol. 1999 Jan;126(1):372-8
references.pmid: 10051158
references.citation: Biochem Biophys Res Commun. 2006 May 5;343(2):361-8
references.pmid: 16545776
references.citation: Biochem J. 2006 Nov 1;399(3):473-81
references.pmid: 16822230
references.citation: Mol Biol Cell. 2010 Aug 1;21(15):2721-31
references.pmid: 20519436
references.citation: Diabetologia. 2009 Oct;52(10):2169-81
references.pmid: 19633828
references.citation: Diabetes. 2002 Feb;51(2):443-8
references.pmid: 11812753
references.citation: Endocrinology. 2006 Jan;147(1):552-61
references.pmid: 16223857
references.citation: J Clin Invest. 1996 Jun 15;97(12):2859-65
references.pmid: 8675698
references.citation: Am J Physiol Endocrinol Metab. 2006 Oct;291(4):E817-28
references.pmid: 16735448
references.citation: J Biol Chem. 2008 Apr 11;283(15):10208-20
references.pmid: 18258592
references.citation: Diabetes. 2002 Sep;51(9):2691-7
references.pmid: 12196460
references.citation: J Cell Physiol. 2008 Nov;217(2):478-85
references.pmid: 18561258
references.citation: Cell Mol Immunol. 2006 Aug;3(4):263-70
references.pmid: 16978534
references.citation: J Biol Chem. 2008 Oct 31;283(44):30311-21
references.pmid: 18713752
references.citation: Hepatology. 2010 Jan;51(1):103-10
references.pmid: 19877183
references.citation: Curr Diab Rep. 2006 Jun;6(3):177-81
references.pmid: 16898568
references.citation: J Clin Invest. 2005 Dec;115(12):3494-505
references.pmid: 16294222
references.citation: Biochem J. 2006 Apr 15;395(2):285-93
references.pmid: 16393139
references.citation: J Biol Chem. 1999 Aug 20;274(34):24202-10
references.pmid: 10446195
references.citation: Diabetes. 2003 Aug;52(8):1943-50
references.pmid: 12882909
references.citation: J Biol Chem. 2008 Apr 25;283(17):11107-16
references.pmid: 18281277
references.citation: J Biol Chem. 2003 Mar 21;278(12):10297-303
references.pmid: 12525490
references.citation: J Biol Chem. 1997 Sep 26;272(39):24145-7
references.pmid: 9305862
references.citation: J Cell Sci. 2006 Jul 1;119(Pt 13):2758-67
references.pmid: 16772339
references.citation: Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):7355-9
references.pmid: 8041794
references.citation: J Biol Chem. 2006 Aug 11;281(32):23191-206
references.pmid: 16737966
references.citation: Diabetes. 2005 May;54(5):1459-67
references.pmid: 15855334
references.citation: Diabetes. 1997 Feb;46(2):169-78
references.pmid: 9000691
references.citation: J Cell Physiol. 2007 Jan;210(1):7-15
references.pmid: 17013887
references.citation: J Biol Chem. 2004 Oct 29;279(44):45304-7
references.pmid: 15364919
references.citation: Cell. 2001 Feb 23;104(4):517-29
references.pmid: 11239409
references.citation: Diabetes. 2007 Jul;56(7):1856-64
references.pmid: 17440174
references.citation: J Biol Chem. 1998 Feb 6;273(6):3582-7
references.pmid: 9452485
references.citation: J Immunol. 2008 Feb 15;180(4):2429-42
references.pmid: 18250452
references.citation: J Chromatogr A. 1995 Apr 21;697(1-2):337-43
references.pmid: 7780577
references.citation: Diabetologia. 2005 May;48(5):954-66
references.pmid: 15834551
references.citation: Diabetes. 1999 Jun;48(6):1270-4
references.pmid: 10342815
references.citation: Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4312-7
references.pmid: 9113986
references.citation: Br J Nutr. 2009 Dec;102(11):1557-63
references.pmid: 19622194
references.citation: Am J Physiol Endocrinol Metab. 2007 Sep;293(3):E783-93
references.pmid: 17550999
references.citation: Am J Physiol Endocrinol Metab. 2008 Dec;295(6):E1307-14
references.pmid: 18840766
references.citation: J Biol Chem. 2007 Mar 23;282(12):9008-16
references.pmid: 17220298
references.citation: J Clin Invest. 2001 Jan;107(2):181-9
references.pmid: 11160134
references.citation: Biochem Biophys Res Commun. 2002 Nov 15;298(5):760-4
references.pmid: 12419319
references.citation: Eur J Biochem. 1996 Jul 1;239(1):1-7
references.pmid: 8706692
references.citation: J Biol Chem. 2003 Oct 10;278(41):39296-302
references.pmid: 12890684
references.citation: J Biol Chem. 2009 Jan 23;284(4):2038-44
references.pmid: 19047061
references.citation: Diabetes. 2006 Oct;55(10):2779-87
references.pmid: 17003343
references.citation: Am J Med. 2006 May;119(5 Suppl 1):S10-6
references.pmid: 16563942
references.citation: Endocr Rev. 2004 Apr;25(2):177-204
references.pmid: 15082519
references.citation: Dev Cell. 2005 Jul;9(1):99-108
references.pmid: 15992544
references.citation: J Clin Endocrinol Metab. 2004 Mar;89(3):1301-11
references.pmid: 15001626
references.citation: Science. 2008 Apr 11;320(5873):246-9
references.pmid: 18292304
references.citation: Am J Physiol Endocrinol Metab. 2009 Jul;297(1):E67-75
references.pmid: 19366875
references.citation: Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5306-11
references.pmid: 11309497
references.citation: Cell Signal. 2005 Nov;17(11):1333-42
references.pmid: 16125053
references.citation: J Biol Chem. 2002 Dec 27;277(52):50230-6
references.pmid: 12006582
references.citation: Exp Clin Endocrinol Diabetes. 1999;107(2):119-25
references.pmid: 10320052
references.citation: Diabetes. 2007 Oct;56(10):2541-6
references.pmid: 17646208
references.citation: Proc Natl Acad Sci U S A. 1994 May 24;91(11):4854-8
references.pmid: 8197147