Hepatic Diacylglycerol-Associated Protein Kinase Cε Translocation Links Hepatic Steatosis to Hepatic Insulin Resistance in Humans

Cell Reports

Volumn 19, Issue 10, 2017, Pages 1997-2004

  ter Horst, Kasper W ^a   Gilijamse, Pim W ^a   Versteeg, Ruth I ^a   Ackermans, Mariette T ^a   Nederveen, Aart J ^a   la Fleur, Susanne E ^a,f   Romijn, Johannes A ^a   Nieuwdorp, Max ^a,b,c   Zhang, Dongyan ^d   Samuel, Varman T ^e   Vatner, Daniel F ^e   Petersen, Kitt F ^e   Shulman, Gerald I ^d,e   Serlie, Mireille J ^a  

^a ACADEMIC MEDICAL CENTER   (Netherlands)

^b VU UNIVERSITY MEDICAL CENTER   (Netherlands)

^c VU UNIVERSITY MEDICAL CENTER   (Netherlands)

^d YALE UNIVERSITY   (United States)

^e YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^f NETHERLANDS INSTITUTE FOR NEUROSCIENCE   (Netherlands)

Author keywords

diacylglycerol; glucose clamp; hepatic glucose production; hepatic steatosis; human; insulin resistance; NAFLD; obesity; protein kinase C

Indexed keywords

DIACYLGLYCEROL; INSULIN; PROTEIN KINASE C EPSILON; TRIACYLGLYCEROL; CERAMIDE; PRKCE PROTEIN, HUMAN;

ADIPOSE TISSUE; ADULT; ARTICLE; CELL MEMBRANE; CONTROLLED STUDY; ENZYME ACTIVATION; FEMALE; HUMAN; HUMAN TISSUE; INSULIN RESISTANCE; LIVER BIOPSY; MAJOR CLINICAL STUDY; MALE; NONALCOHOLIC FATTY LIVER; OBESITY; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN TRANSPORT; METABOLISM; PATHOLOGY;

CERAMIDES; DIGLYCERIDES; ENZYME ACTIVATION; FEMALE; HUMANS; INSULIN RESISTANCE; MALE; NON-ALCOHOLIC FATTY LIVER DISEASE; PROTEIN KINASE C-EPSILON; PROTEIN TRANSPORT;

EID: 85020297753     PISSN: None     EISSN: 22111247     Source Type: Journal    
DOI: 10.1016/j.celrep.2017.05.035     Document Type: Article

References (50)

1. Ackermans, M.T., Pereira Arias, A.M., Bisschop, P.H., Endert, E., Sauerwein, H.P., Romijn, J.A., The quantification of gluconeogenesis in healthy men by (2)H2O and [2-(13)C]glycerol yields different results: Rates of gluconeogenesis in healthy men measured with (2)H2O are higher than those measured with [2-(13)C]glycerol. J. Clin. Endocrinol. Metab. 86 (2001), 2220–2226.
2. Amaro, A., Fabbrini, E., Kars, M., Yue, P., Schechtman, K., Schonfeld, G., Klein, S., Dissociation between intrahepatic triglyceride content and insulin resistance in familial hypobetalipoproteinemia. Gastroenterology 139 (2010), 149–153.
3. Benhamed, F., Denechaud, P.D., Lemoine, M., Robichon, C., Moldes, M., Bertrand-Michel, J., Ratziu, V., Serfaty, L., Housset, C., Capeau, J., et al. The lipogenic transcription factor ChREBP dissociates hepatic steatosis from insulin resistance in mice and humans. J. Clin. Invest. 122 (2012), 2176–2194.
4. Brown, J.M., Betters, J.L., Lord, C., Ma, Y., Han, X., Yang, K., Alger, H.M., Melchior, J., Sawyer, J., Shah, R., et al. CGI-58 knockdown in mice causes hepatic steatosis but prevents diet-induced obesity and glucose intolerance. J. Lipid Res. 51 (2010), 3306–3315.
5. Buettner, R., Ottinger, I., Schölmerich, J., Bollheimer, L.C., Preserved direct hepatic insulin action in rats with diet-induced hepatic steatosis. Am. J. Physiol. Endocrinol. Metab. 286 (2004), E828–E833.
6. Bugianesi, E., Gastaldelli, A., Vanni, E., Gambino, R., Cassader, M., Baldi, S., Ponti, V., Pagano, G., Ferrannini, E., Rizzetto, M., Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: Sites and mechanisms. Diabetologia 48 (2005), 634–642.
7. Cantley, J.L., Yoshimura, T., Camporez, J.P., Zhang, D., Jornayvaz, F.R., Kumashiro, N., Guebre-Egziabher, F., Jurczak, M.J., Kahn, M., Guigni, B.A., et al. CGI-58 knockdown sequesters diacylglycerols in lipid droplets/ER-preventing diacylglycerol-mediated hepatic insulin resistance. Proc. Natl. Acad. Sci. USA 110 (2013), 1869–1874.
8. Chavez, J.A., Summers, S.A., A ceramide-centric view of insulin resistance. Cell Metab. 15 (2012), 585–594.
9. Cohen, J.C., Horton, J.D., Hobbs, H.H., Human fatty liver disease: Old questions and new insights. Science 332 (2011), 1519–1523.
10. Deivanayagam, S., Mohammed, B.S., Vitola, B.E., Naguib, G.H., Keshen, T.H., Kirk, E.P., Klein, S., Nonalcoholic fatty liver disease is associated with hepatic and skeletal muscle insulin resistance in overweight adolescents. Am. J. Clin. Nutr. 88 (2008), 257–262.
11. Donnelly, K.L., Smith, C.I., Schwarzenberg, S.J., Jessurun, J., Boldt, M.D., Parks, E.J., Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J. Clin. Invest. 115 (2005), 1343–1351.
12. Dulai, P.S., Sirlin, C.B., Loomba, R., MRI and MRE for non-invasive quantitative assessment of hepatic steatosis and fibrosis in NAFLD and NASH: Clinical trials to clinical practice. J. Hepatol. 65 (2016), 1006–1016.
13. Farese, R.V. Jr., Zechner, R., Newgard, C.B., Walther, T.C., The problem of establishing relationships between hepatic steatosis and hepatic insulin resistance. Cell Metab. 15 (2012), 570–573.
14. Finck, B.N., Hall, A.M., Does diacylglycerol accumulation in fatty liver disease cause hepatic insulin resistance?. BioMed Res. Int., 2015, 2015, 104132.
15. Gastaldelli, A., Cusi, K., Pettiti, M., Hardies, J., Miyazaki, Y., Berria, R., Buzzigoli, E., Sironi, A.M., Cersosimo, E., Ferrannini, E., Defronzo, R.A., Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects. Gastroenterology 133 (2007), 496–506.
16. Grundy, S.M., Metabolic complications of obesity. Endocrine 13 (2000), 155–165.
17. Holland, W.L., Miller, R.A., Wang, Z.V., Sun, K., Barth, B.M., Bui, H.H., Davis, K.E., Bikman, B.T., Halberg, N., Rutkowski, J.M., et al. Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nat. Med. 17 (2011), 55–63.
18. Jornayvaz, F.R., Birkenfeld, A.L., Jurczak, M.J., Kanda, S., Guigni, B.A., Jiang, D.C., Zhang, D., Lee, H.Y., Samuel, V.T., Shulman, G.I., Hepatic insulin resistance in mice with hepatic overexpression of diacylglycerol acyltransferase 2. Proc. Natl. Acad. Sci. USA 108 (2011), 5748–5752.
19. Korenblat, K.M., Fabbrini, E., Mohammed, B.S., Klein, S., Liver, muscle, and adipose tissue insulin action is directly related to intrahepatic triglyceride content in obese subjects. Gastroenterology 134 (2008), 1369–1375.
20. Kotronen, A., Juurinen, L., Tiikkainen, M., Vehkavaara, S., Yki-Järvinen, H., Increased liver fat, impaired insulin clearance, and hepatic and adipose tissue insulin resistance in type 2 diabetes. Gastroenterology 135 (2008), 122–130.
21. Kumashiro, N., Erion, D.M., Zhang, D., Kahn, M., Beddow, S.A., Chu, X., Still, C.D., Gerhard, G.S., Han, X., Dziura, J., et al. Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease. Proc. Natl. Acad. Sci. USA 108 (2011), 16381–16385.
22. Luukkonen, P.K., Zhou, Y., Sädevirta, S., Leivonen, M., Arola, J., Orešič, M., Hyötyläinen, T., Yki-Järvinen, H., Hepatic ceramides dissociate steatosis and insulin resistance in patients with non-alcoholic fatty liver disease. J. Hepatol. 64 (2016), 1167–1175.
23. Magkos, F., Su, X., Bradley, D., Fabbrini, E., Conte, C., Eagon, J.C., Varela, J.E., Brunt, E.M., Patterson, B.W., Klein, S., Intrahepatic diacylglycerol content is associated with hepatic insulin resistance in obese subjects. Gastroenterology, 142, 2012 1444–6.e2.
24. Monetti, M., Levin, M.C., Watt, M.J., Sajan, M.P., Marmor, S., Hubbard, B.K., Stevens, R.D., Bain, J.R., Newgard, C.B., Farese, R.V. Sr., et al. Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver. Cell Metab. 6 (2007), 69–78.
25. Nagle, C.A., Klett, E.L., Coleman, R.A., Hepatic triacylglycerol accumulation and insulin resistance. J. Lipid Res. 50:Suppl (2009), S74–S79.
26. Perry, R.J., Kim, T., Zhang, X.M., Lee, H.Y., Pesta, D., Popov, V.B., Zhang, D., Rahimi, Y., Jurczak, M.J., Cline, G.W., et al. Reversal of hypertriglyceridemia, fatty liver disease, and insulin resistance by a liver-targeted mitochondrial uncoupler. Cell Metab. 18 (2013), 740–748.
27. Perry, R.J., Samuel, V.T., Petersen, K.F., Shulman, G.I., The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes. Nature 510 (2014), 84–91.
28. Perry, R.J., Camporez, J.P., Kursawe, R., Titchenell, P.M., Zhang, D., Perry, C.J., Jurczak, M.J., Abudukadier, A., Han, M.S., Zhang, X.M., et al. Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes. Cell 160 (2015), 745–758.
29. Petersen, K.F., Oral, E.A., Dufour, S., Befroy, D., Ariyan, C., Yu, C., Cline, G.W., DePaoli, A.M., Taylor, S.I., Gorden, P., Shulman, G.I., Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J. Clin. Invest. 109 (2002), 1345–1350.
30. Petersen, K.F., Dufour, S., Befroy, D., Lehrke, M., Hendler, R.E., Shulman, G.I., Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes 54 (2005), 603–608.
31. Petersen, K.F., Dufour, S., Savage, D.B., Bilz, S., Solomon, G., Yonemitsu, S., Cline, G.W., Befroy, D., Zemany, L., Kahn, B.B., et al. The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome. Proc. Natl. Acad. Sci. USA 104 (2007), 12587–12594.
32. Petersen, M.C., Madiraju, A.K., Gassaway, B.M., Marcel, M., Nasiri, A.R., Butrico, G., Marcucci, M.J., Zhang, D., Abulizi, A., Zhang, X.M., et al. Insulin receptor Thr1160 phosphorylation mediates lipid-induced hepatic insulin resistance. J. Clin. Invest. 126 (2016), 4361–4371.
33. Rabøl, R., Petersen, K.F., Dufour, S., Flannery, C., Shulman, G.I., Reversal of muscle insulin resistance with exercise reduces postprandial hepatic de novo lipogenesis in insulin resistant individuals. Proc. Natl. Acad. Sci. USA 108 (2011), 13705–13709.
34. Samuel, V.T., Shulman, G.I., The pathogenesis of insulin resistance: Integrating signaling pathways and substrate flux. J. Clin. Invest. 126 (2016), 12–22.
35. Samuel, V.T., Liu, Z.X., Qu, X., Elder, B.D., Bilz, S., Befroy, D., Romanelli, A.J., Shulman, G.I., Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J. Biol. Chem. 279 (2004), 32345–32353.
36. Samuel, V.T., Liu, Z.X., Wang, A., Beddow, S.A., Geisler, J.G., Kahn, M., Zhang, X.M., Monia, B.P., Bhanot, S., Shulman, G.I., Inhibition of protein kinase Cepsilon prevents hepatic insulin resistance in nonalcoholic fatty liver disease. J. Clin. Invest. 117 (2007), 739–745.
37. Sanyal, A.J., Campbell-Sargent, C., Mirshahi, F., Rizzo, W.B., Contos, M.J., Sterling, R.K., Luketic, V.A., Shiffman, M.L., Clore, J.N., Nonalcoholic steatohepatitis: Association of insulin resistance and mitochondrial abnormalities. Gastroenterology 120 (2001), 1183–1192.
38. Schmitz-Peiffer, C., Biden, T.J., Protein kinase C function in muscle, liver, and beta-cells and its therapeutic implications for type 2 diabetes. Diabetes 57 (2008), 1774–1783.
39. Semple, R.K., Sleigh, A., Murgatroyd, P.R., Adams, C.A., Bluck, L., Jackson, S., Vottero, A., Kanabar, D., Charlton-Menys, V., Durrington, P., et al. Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis. J. Clin. Invest. 119 (2009), 315–322.
40. Seppälä-Lindroos, A., Vehkavaara, S., Häkkinen, A.M., Goto, T., Westerbacka, J., Sovijärvi, A., Halavaara, J., Yki-Järvinen, H., Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. J. Clin. Endocrinol. Metab. 87 (2002), 3023–3028.
41. Shulman, G.I., Cellular mechanisms of insulin resistance. J. Clin. Invest. 106 (2000), 171–176.
42. Steele, R., Influences of glucose loading and of injected insulin on hepatic glucose output. Ann. N Y Acad. Sci. 82 (1959), 420–430.
43. Szczepaniak, L.S., Nurenberg, P., Leonard, D., Browning, J.D., Reingold, J.S., Grundy, S., Hobbs, H.H., Dobbins, R.L., Magnetic resonance spectroscopy to measure hepatic triglyceride content: Prevalence of hepatic steatosis in the general population. Am. J. Physiol. Endocrinol. Metab. 288 (2005), E462–E468.
44. ter Horst, K.W., Gilijamse, P.W., Koopman, K.E., de Weijer, B.A., Brands, M., Kootte, R.S., Romijn, J.A., Ackermans, M.T., Nieuwdorp, M., Soeters, M.R., Serlie, M.J., Insulin resistance in obesity can be reliably identified from fasting plasma insulin. Int. J. Obes. 39 (2015), 1703–1709.
45. van der Valk, F., Hassing, C., Visser, M., Thakkar, P., Mohanan, A., Pathak, K., Dutt, C., Chauthaiwale, V., Ackermans, M., Nederveen, A., et al. The effect of a diiodothyronine mimetic on insulin sensitivity in male cardiometabolic patients: A double-blind randomized controlled trial. PLoS ONE, 9, 2014, e86890.
46. Vatner, D.F., Majumdar, S.K., Kumashiro, N., Petersen, M.C., Rahimi, Y., Gattu, A.K., Bears, M., Camporez, J.P., Cline, G.W., Jurczak, M.J., et al. Insulin-independent regulation of hepatic triglyceride synthesis by fatty acids. Proc. Natl. Acad. Sci. USA 112 (2015), 1143–1148.
47. Visser, M.E., Lammers, N.M., Nederveen, A.J., van der Graaf, M., Heerschap, A., Ackermans, M.T., Sauerwein, H.P., Stroes, E.S., Serlie, M.J., Hepatic steatosis does not cause insulin resistance in people with familial hypobetalipoproteinaemia. Diabetologia 54 (2011), 2113–2121.
48. Wong, R.J., Cheung, R., Ahmed, A., Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U.S. Hepatology 59 (2014), 2188–2195.
49. Xia, J.Y., Holland, W.L., Kusminski, C.M., Sun, K., Sharma, A.X., Pearson, M.J., Sifuentes, A.J., McDonald, J.G., Gordillo, R., Scherer, P.E., Targeted induction of ceramide degradation leads to improved systemic metabolism and reduced hepatic steatosis. Cell Metab. 22 (2015), 266–278.
50. Yu, C., Chen, Y., Cline, G.W., Zhang, D., Zong, H., Wang, Y., Bergeron, R., Kim, J.K., Cushman, S.W., Cooney, G.J., et al. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J. Biol. Chem. 277 (2002), 50230–50236.