Skip to main content
SpringerLink
Log in

Diabetes and apoptosis: liver

  • Diabetes and Apoptosis
  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

The liver is a central regulator of glucose homeostasis and stores or releases glucose according to metabolic demands. In insulin resistant states or diabetes the dysregulation of hepatic glucose release contributes significantly to the pathophysiology of these conditions. Acute or chronic liver disease can aggravate insulin resistance and the physiological effects of insulin on hepatocytes are disturbed. Insulin resistance has also been recognized as an independent risk factor for the development of liver injury. In the healthy liver tissue homeostasis is achieved through cell turnover by apoptosis and dysregulation of the physiological process resulting in too much or too little cell death can have potentially devastating effects on liver tissue. The delineation of the signaling pathways that mediate apoptosis changed the paradigms of understanding of many liver diseases. These signaling events include cell surface based receptor-ligand systems and intracellular signaling pathways that are regulated through kinases on multiple levels. The dissection of these signaling pathways has shown that the regulators of apoptosis signaling events in hepatocytes can also modulate insulin signaling pathways and that mediators of insulin resistance in turn influence liver cell apoptosis. This review will summarize the potential crosstalk between apoptosis and insulin resistance signaling events and discuss the involved mediators.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

AMPK:

5′AMP-activated protein kinase

CCl4 :

Carbon-tetrachloride

Erk:

Extracellular-regulated kinase

FADD:

Fas-associated death domain

gal:

Galactosamine

GSK3:

Glycogen synthase kinase 3

HCV:

Hepatitis C virus

HCC:

Hepatocellular carcinoma

HSC:

Hepatic stellate cells

IKK:

IκB kinase

iNOS:

Inducible nitric-oxide synthase

LPS:

Lipopolysaccharide

IL:

Interleukin

IRS:

Insulin receptor substrate

JAKs:

Janus kinases

JNK:

c-Jun N-terminal kinase

MAPK:

Mitogen-activated protein kinases

mTOR:

Mammalian target of rapamycin

NASH:

Non-alcoholic steatohepatitis

NF-κB:

Nuclear factor-κB

NKT:

Natural killer T cells

PARP-1:

Poly-(ADP-ribose) polymerase-1

PI3 K:

Phosphoinositide 3-kinase

PPAR-α:

Peroxisome proliferator-activated receptor-α

PKC:

Protein kinase C

SOCS:

Suppressors of cytokine signaling

SREBP:

Sterol regulatory element-binding protein

STAT:

Signal transducers and activators of transcription

TGFβ:

Transforming growth factor β

TNF:

Tumor necrosis factor α

References

  1. James PT, Rigby N, Leach R (2004) The obesity epidemic, metabolic syndrome and future prevention strategies. Eur J Cardiovasc Prev Rehabil 11:3–8. doi:10.1097/01.hjr.0000114707.27531.48

    Article  PubMed  Google Scholar 

  2. Reaven GM (1988) Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 37:1595–1607. doi:10.2337/diabetes.37.12.1595

    Article  PubMed  CAS  Google Scholar 

  3. Ford ES, Giles WH, Mokdad AH (2004) Increasing prevalence of the metabolic syndrome among US adults. Diabetes Care 27:2444–2449. doi:10.2337/diacare.27.10.2444

    Article  PubMed  Google Scholar 

  4. Cornier MA, Dabelea D, Hernandez TL et al (2008) The metabolic syndrome. Endocr Rev 29:777–822. doi:10.1210/er.2008-0024

    Article  PubMed  CAS  Google Scholar 

  5. Martinez MA, Puig JG, Mora M et al (2008) Metabolic syndrome: prevalence, associated factors, and C-reactive protein: the MADRIC (MADrid RIesgo Cardiovascular) study. Metabolism 57:1232–1240. doi:10.1016/j.metabol.2008.04.017

    Article  PubMed  CAS  Google Scholar 

  6. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (2001) Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). JAMA 285:2486–2497. doi:10.1001/jama.285.19.2486

    Article  Google Scholar 

  7. Low AK, Bouldin MJ, Sumrall CD, Loustalot FV, Land KK (2006) A clinician’s approach to medical management of obesity. Am J Med Sci 331:175–182. doi:10.1097/00000441-200604000-00003

    Article  PubMed  Google Scholar 

  8. Takamatsu S, Noguchi N, Kudoh A et al (2008) Influence of risk factors for metabolic syndrome and non-alcoholic fatty liver disease on the progression and prognosis of hepatocellular carcinoma. Hepatogastroenterology 55:609–614

    PubMed  Google Scholar 

  9. Harrison SA (2008) Insulin resistance among patients with chronic hepatitis C: etiology and impact on treatment. Clin Gastroenterol Hepatol 6:864–876. doi:10.1016/j.cgh.2008.03.024

    Article  PubMed  Google Scholar 

  10. Marchesini G, Marzocchi R (2007) Metabolic syndrome and NASH. Clin Liver Dis 11:105–117. doi:10.1016/j.cld.2007.02.013

    Article  PubMed  Google Scholar 

  11. Ban CR, Twigg SM (2008) Fibrosis in diabetes complications: pathogenic mechanisms and circulating and urinary markers. Vasc Health Risk Manag 4:575–596

    PubMed  CAS  Google Scholar 

  12. Bugianesi E, McCullough AJ, Marchesini G (2005) Insulin resistance: a metabolic pathway to chronic liver disease. Hepatology 42:987–1000. doi:10.1002/hep.20920

    Article  PubMed  CAS  Google Scholar 

  13. Ratziu V, Giral P, Charlotte F et al (2000) Liver fibrosis in overweight patients. Gastroenterology 118:1117–1123. doi:10.1016/S0016-5085(00)70364-7

    Article  PubMed  CAS  Google Scholar 

  14. Kuwahata M, Tomoe Y, Harada N et al (2007) Characterization of the molecular mechanisms involved in the increased insulin secretion in rats with acute liver failure. Biochim Biophys Acta 1772:60–65. doi:10.1016/j.bbadis.2006.10.001

    PubMed  CAS  Google Scholar 

  15. Adiels M, Taskinen MR, Boren J (2008) Fatty liver, insulin resistance, and dyslipidemia. Curr Diab Rep 8:60–64. doi:10.1007/s11892-008-0011-4

    Article  PubMed  CAS  Google Scholar 

  16. Korenblat KM, Fabbrini E, Mohammed BS, Klein S (2008) Liver, muscle, and adipose tissue insulin action is directly related to intrahepatic triglyceride content in obese subjects. Gastroenterology 134:1369–1375. doi:10.1053/j.gastro.2008.01.075

    Article  PubMed  CAS  Google Scholar 

  17. White MF (2002) IRS proteins and the common path to diabetes. Am J Physiol Endocrinol Metab 283:E413–E422. doi:10.1152/ajpendo.00514.2001

    PubMed  CAS  Google Scholar 

  18. Kido Y, Burks DJ, Withers D, Bruning JC, Kahn CR, White MF, Accili D (2000) Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2. J Clin Invest 105:199–205. doi:10.1172/JCI7917

    Article  PubMed  CAS  Google Scholar 

  19. Valverde AM, Burks DJ, Fabregat I, Fisher TL, Carretero J, White MF, Benito M (2003) Molecular mechanisms of insulin resistance in IRS-2-deficient hepatocytes. Diabetes 52:2239–2248. doi:10.2337/diabetes.52.9.2239

    Article  PubMed  CAS  Google Scholar 

  20. Saltiel AR, Kahn CR (2001) Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414:799–806. doi:10.1038/414799a

    Article  PubMed  CAS  Google Scholar 

  21. Shulman GI (2000) Cellular mechanisms of insulin resistance. J Clin Invest 106:171–176. doi:10.1172/JCI10583

    Article  PubMed  CAS  Google Scholar 

  22. Lee YH, Giraud J, Davis RJ, White MF (2003) c-Jun N-terminal kinase (JNK) mediates feedback inhibition of the insulin signaling cascade. J Biol Chem 278:2896–2902. doi:10.1074/jbc.M208359200

    Article  PubMed  CAS  Google Scholar 

  23. Greene MW, Morrice N, Garofalo RS, Roth RA (2004) Modulation of human insulin receptor substrate-1 tyrosine phosphorylation by protein kinase Cdelta. Biochem J 378:105–116. doi:10.1042/BJ20031493

    Article  PubMed  CAS  Google Scholar 

  24. Liu YF, Paz K, Herschkovitz A et al (2001) Insulin stimulates PKCzeta -mediated phosphorylation of insulin receptor substrate-1 (IRS-1). A self-attenuated mechanism to negatively regulate the function of IRS proteins. J Biol Chem 276:14459–14465. doi:10.1074/jbc.M007281200

    PubMed  CAS  Google Scholar 

  25. Gual P, Gonzalez T, Gremeaux T, Barres R, Marchand-Brustel Y, Tanti JF (2003) Hyperosmotic stress inhibits insulin receptor substrate-1 function by distinct mechanisms in 3T3–L1 adipocytes. J Biol Chem 278:26550–26557. doi:10.1074/jbc.M212273200

    Article  PubMed  CAS  Google Scholar 

  26. Giraud J, Leshan R, Lee YH, White MF (2004) Nutrient-dependent and insulin-stimulated phosphorylation of insulin receptor substrate-1 on serine 302 correlates with increased insulin signaling. J Biol Chem 279:3447–3454. doi:10.1074/jbc.M308631200

    Article  PubMed  CAS  Google Scholar 

  27. Gao Z, Hwang D, Bataille F, Lefevre M, York D, Quon MJ, Ye J (2002) Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex. J Biol Chem 277:48115–48121. doi:10.1074/jbc.M209459200

    Article  PubMed  CAS  Google Scholar 

  28. Sugita H, Fujimoto M, Yasukawa T et al (2005) Inducible nitric-oxide synthase and NO donor induce insulin receptor substrate-1 degradation in skeletal muscle cells. J Biol Chem 280:14203–14211. doi:10.1074/jbc.M411226200

    Article  PubMed  CAS  Google Scholar 

  29. Carvalho-Filho MA, Ueno M, Hirabara SM et al (2005) S-nitrosation of the insulin receptor, insulin receptor substrate 1, and protein kinase B/Akt: a novel mechanism of insulin resistance. Diabetes 54:959–967. doi:10.2337/diabetes.54.4.959

    Article  PubMed  CAS  Google Scholar 

  30. Shi H, Cave B, Inouye K, Bjorbaek C, Flier JS (2006) Overexpression of suppressor of cytokine signaling 3 in adipose tissue causes local but not systemic insulin resistance. Diabetes 55:699–707. doi:10.2337/diabetes.55.03.06.db05-0841

    Article  PubMed  CAS  Google Scholar 

  31. Cho H, Mu J, Kim JK et al (2001) Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science 292:1728–1731. doi:10.1126/science.292.5522.1728

    Article  PubMed  CAS  Google Scholar 

  32. Nakae J, Biggs WHIII, Kitamura T, Cavenee WK, Wright CV, Arden KC, Accili D (2002) Regulation of insulin action and pancreatic beta-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1. Nat Genet 32:245–253. doi:10.1038/ng890

    Article  PubMed  CAS  Google Scholar 

  33. Zhang W, Patil S, Chauhan B et al (2006) FoxO1 regulates multiple metabolic pathways in the liver: effects on gluconeogenic, glycolytic, and lipogenic gene expression. J Biol Chem 281:10105–10117. doi:10.1074/jbc.M600272200

    Article  PubMed  CAS  Google Scholar 

  34. Schattenberg JM, Galle PR, Schuchmann M (2006) Apoptosis in liver disease. Liver Int 26:904–911. doi:10.1111/j.1478-3231.2006.01324.x

    Article  PubMed  CAS  Google Scholar 

  35. Malhi H, Gores GJ (2008) Cellular and molecular mechanisms of liver injury. Gastroenterology 134:1641–1654. doi:10.1053/j.gastro.2008.03.002

    Article  PubMed  CAS  Google Scholar 

  36. Friedman SL (2008) Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 88:125–172. doi:10.1152/physrev.00013.2007

    Article  PubMed  CAS  Google Scholar 

  37. Schulze-Bergkamen H, Schuchmann M, Fleischer B, Galle PR (2006) The role of apoptosis versus oncotic necrosis in liver injury: facts or faith? J Hepatol 44:984–993. doi:10.1016/j.jhep.2006.02.004

    Article  PubMed  CAS  Google Scholar 

  38. Yin XM, Ding WX, Gao W (2008) Autophagy in the liver. Hepatology 47:1773–1785. doi:10.1002/hep.22146

    Article  PubMed  CAS  Google Scholar 

  39. Park DR, Thomsen AR, Frevert CW, Pham U, Skerrett SJ, Kiener PA, Liles WC (2003) Fas (CD95) induces proinflammatory cytokine responses by human monocytes and monocyte-derived macrophages. J Immunol 170:6209–6216

    PubMed  CAS  Google Scholar 

  40. Loffreda S, Rai R, Yang SQ, Lin HZ, Diehl AM (1997) Bile ducts and portal and central veins are major producers of tumor necrosis factor alpha in regenerating rat liver. Gastroenterology 112:2089–2098. doi:10.1053/gast.1997.v112.pm9178702

    Article  PubMed  CAS  Google Scholar 

  41. Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G (2001) Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab 280:E745–E751

    PubMed  CAS  Google Scholar 

  42. Schattenberg JM, Czaja MJ (2005) Nature and function of hepatic tumor necrosis factor-α signaling. In: Dufour JF, Clavien P-A (eds) Signaling pathways in liver diseases. Springer Verlag, Berlin, pp 115–128

    Chapter  Google Scholar 

  43. Micheau O, Tschopp J (2003) Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 114:181–190. doi:10.1016/S0092-8674(03)00521-X

    Article  PubMed  CAS  Google Scholar 

  44. Wajant H, Pfizenmaier K, Scheurich P (2003) Tumor necrosis factor signaling. Cell Death Differ 10:45–65. doi:10.1038/sj.cdd.4401189

    Article  PubMed  CAS  Google Scholar 

  45. Ashkenazi A, Dixit VM (1999) Apoptosis control by death and decoy receptors. Curr Opin Cell Biol 11:255–260. doi:10.1016/S0955-0674(99)80034-9

    Article  PubMed  CAS  Google Scholar 

  46. Wullaert A, van Loo G, Heyninck K, Beyaert R (2007) Hepatic tumor necrosis factor signaling and nuclear factor-kappaB: effects on liver homeostasis and beyond. Endocr Rev 28:365–386. doi:10.1210/er.2006-0031

    Article  PubMed  CAS  Google Scholar 

  47. Peter ME, Krammer PH (2003) The CD95(APO-1/Fas) DISC and beyond. Cell Death Differ 10:26–35. doi:10.1038/sj.cdd.4401186

    Article  PubMed  CAS  Google Scholar 

  48. Bhardwaj A, Aggarwal BB (2003) Receptor-mediated choreography of life and death. J Clin Immunol 23:317–332. doi:10.1023/A:1025319031417

    Article  PubMed  CAS  Google Scholar 

  49. Chinnaiyan AM, Tepper CG, Seldin MF et al (1996) FADD/MORT1 is a common mediator of CD95 (Fas/APO-1) and tumor necrosis factor receptor-induced apoptosis. J Biol Chem 271:4961–4965. doi:10.1074/jbc.271.9.4961

    Article  PubMed  CAS  Google Scholar 

  50. Walter D, Schmich K, Vogel S et al (2008) Switch from type II to I Fas/CD95 death signaling on in vitro culturing of primary hepatocytes. Hepatology 48:1942–1953. doi:10.1002/hep.22541

    Article  PubMed  CAS  Google Scholar 

  51. Varfolomeev E, Maecker H, Sharp D, Lawrence D, Renz M, Vucic D, Ashkenazi A (2005) Molecular determinants of kinase pathway activation by Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand. J Biol Chem 280:40599–40608. doi:10.1074/jbc.M509560200

    Article  PubMed  CAS  Google Scholar 

  52. Ea CK, Deng L, Xia ZP, Pineda G, Chen ZJ (2006) Activation of IKK by TNFalpha requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO. Mol Cell 22:245–257. doi:10.1016/j.molcel.2006.03.026

    Article  PubMed  CAS  Google Scholar 

  53. Karin M (2006) Nuclear factor-kappaB in cancer development and progression. Nature 441:431–436. doi:10.1038/nature04870

    Article  PubMed  CAS  Google Scholar 

  54. Micheau O, Lens S, Gaide O, Alevizopoulos K, Tschopp J (2001) NF-kappaB signals induce the expression of c-FLIP. Mol Cell Biol 21:5299–5305. doi:10.1128/MCB.21.16.5299-5305.2001

    Article  PubMed  CAS  Google Scholar 

  55. Chen C, Edelstein LC, Gelinas C (2000) The Rel/NF-kappaB family directly activates expression of the apoptosis inhibitor Bcl-x(L). Mol Cell Biol 20:2687–2695. doi:10.1128/MCB.20.8.2687-2695.2000

    Article  PubMed  Google Scholar 

  56. Xu Y, Bialik S, Jones BE et al (1998) NF-kappaB inactivation converts a hepatocyte cell line TNF-alpha response from proliferation to apoptosis. Am J Physiol 275:C1058–C1066

    PubMed  CAS  Google Scholar 

  57. Baehrecke EH (2005) Autophagy: dual roles in life and death? Nat Rev Mol Cell Biol 6:505–510. doi:10.1038/nrm1666

    Article  PubMed  CAS  Google Scholar 

  58. Sondergaard L (1993) Homology between the mammalian liver and the Drosophila fat body. Trends Genet 9:193. doi:10.1016/0168-9525(93)90113-V

    Article  PubMed  CAS  Google Scholar 

  59. Leclerc V, Reichhart JM (2004) The immune response of Drosophila melanogaster. Immunol Rev 198:59–71. doi:10.1111/j.0105-2896.2004.0130.x

    Article  PubMed  CAS  Google Scholar 

  60. Hotamisligil GS, Shargill NS, Spiegelman BM (1993) Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259:87–91. doi:10.1126/science.7678183

    Article  PubMed  CAS  Google Scholar 

  61. Tilg H, Moschen AR (2008) Inflammatory mechanisms in the regulation of insulin resistance. Mol Med 14:222–231. doi:10.2119/2007-00119.Tilg

    Article  PubMed  CAS  Google Scholar 

  62. Dejager L, Libert C (2008) Tumor necrosis factor alpha mediates the lethal hepatotoxic effects of poly(I:C) in d-galactosamine-sensitized mice. Cytokine 42:55–61. doi:10.1016/j.cyto.2008.01.014

    Article  PubMed  CAS  Google Scholar 

  63. Czaja MJ, Xu J, Alt E (1995) Prevention of carbon tetrachloride-induced rat liver injury by soluble tumor necrosis factor receptor. Gastroenterology 108:1849–1854. doi:10.1016/0016-5085(95)90149-3

    Article  PubMed  CAS  Google Scholar 

  64. Cressman DE, Greenbaum LE, DeAngelis RA, Ciliberto G, Furth EE, Poli V, Taub R (1996) Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science 274:1379–1383. doi:10.1126/science.274.5291.1379

    Article  PubMed  CAS  Google Scholar 

  65. Yamada Y, Kirillova I, Peschon JJ, Fausto N (1997) Initiation of liver growth by tumor necrosis factor: deficient liver regeneration in mice lacking type I tumor necrosis factor receptor. Proc Natl Acad Sci USA 94:1441–1446. doi:10.1073/pnas.94.4.1441

    Article  PubMed  CAS  Google Scholar 

  66. Yared G, Hussain KB, Nathani MG, Moshier JA, Dosescu J, Mutchnick MG, Naylor PH (1998) Cytokine-mediated apoptosis and inhibition of virus production and anchorage independent growth of viral transfected hepatoblastoma cells. Cytokine 10:586–595. doi:10.1006/cyto.1998.0340

    Article  PubMed  CAS  Google Scholar 

  67. Biermer M, Puro R, Schneider RJ (2003) Tumor necrosis factor alpha inhibition of hepatitis B virus replication involves disruption of capsid Integrity through activation of NF-kappaB. J Virol 77:4033–4042. doi:10.1128/JVI.77.7.4033-4042.2003

    Article  PubMed  CAS  Google Scholar 

  68. Hotamisligil GS (1999) Mechanisms of TNF-alpha-induced insulin resistance. Exp Clin Endocrinol Diabetes 107:119–125

    Article  PubMed  CAS  Google Scholar 

  69. Feldstein AE, Canbay A, Angulo P, Taniai M, Burgart LJ, Lindor KD, Gores GJ (2003) Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology 125:437–443. doi:10.1016/S0016-5085(03)00907-7

    Article  PubMed  Google Scholar 

  70. Crespo J, Cayon A, Fernandez-Gil P et al (2001) Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology 34:1158–1163. doi:10.1053/jhep.2001.29628

    Article  PubMed  CAS  Google Scholar 

  71. Karin M, Gallagher E (2009) TNFR signaling: ubiquitin-conjugated TRAFfic signals control stop-and-go for MAPK signaling complexes. Immunol Rev 228:225–240. doi:10.1111/j.1600-065X.2008.00755.x

    Article  PubMed  Google Scholar 

  72. Wilson NS, Dixit V, Ashkenazi A (2009) Death receptor signal transducers: nodes of coordination in immune signaling networks. Nat Immunol 10:348–355. doi:10.1038/ni.1714

    Article  PubMed  CAS  Google Scholar 

  73. Di Gregorio GB, Yao-Borengasser A, Rasouli N et al (2005) Expression of CD68 and macrophage chemoattractant protein-1 genes in human adipose and muscle tissues: association with cytokine expression, insulin resistance, and reduction by pioglitazone. Diabetes 54:2305–2313. doi:10.2337/diabetes.54.8.2305

    Article  PubMed  CAS  Google Scholar 

  74. Suganami T, Nishida J, Ogawa Y (2005) A paracrine loop between adipocytes and macrophages aggravates inflammatory changes: role of free fatty acids and tumor necrosis factor alpha. Arterioscler Thromb Vasc Biol 25:2062–2068. doi:10.1161/01.ATV.0000183883.72263.13

    Article  PubMed  CAS  Google Scholar 

  75. Rabe K, Lehrke M, Parhofer KG, Broedl UC (2008) Adipokines and insulin resistance. Mol Med 14:741–751. doi:10.2119/2008-00058.Rabe

    Article  PubMed  CAS  Google Scholar 

  76. Olleros ML, Martin ML, Vesin D et al (2008) Fat diet and alcohol-induced steatohepatitis after LPS challenge in mice: role of bioactive TNF and Th1 type cytokines. Cytokine 44:118–125. doi:10.1016/j.cyto.2008.07.001

    Article  PubMed  CAS  Google Scholar 

  77. Bigorgne AE, Bouchet-Delbos L, Naveau S et al (2008) Obesity-induced lymphocyte hyperresponsiveness to chemokines: a new mechanism of Fatty liver inflammation in obese mice. Gastroenterology 134:1459–1469. doi:10.1053/j.gastro.2008.02.055

    Article  PubMed  Google Scholar 

  78. Rao RK, Seth A, Sheth P (2004) Recent advances in alcoholic liver disease I. Role of intestinal permeability and endotoxemia in alcoholic liver disease. Am J Physiol Gastrointest Liver Physiol 286:G881–G884. doi:10.1152/ajpgi.00006.2004

    Article  PubMed  CAS  Google Scholar 

  79. Karin M (2008) The IkappaB kinase—a bridge between inflammation and cancer. Cell Res 18:334–342. doi:10.1038/cr.2008.30

    Article  PubMed  CAS  Google Scholar 

  80. Leitges M, Sanz L, Martin P et al (2001) Targeted disruption of the zetaPKC gene results in the impairment of the NF-kappaB pathway. Mol Cell 8:771–780. doi:10.1016/S1097-2765(01)00361-6

    Article  PubMed  CAS  Google Scholar 

  81. Oliver FJ, Menissier-de Murcia J, Nacci C et al (1999) Resistance to endotoxic shock as a consequence of defective NF-kappaB activation in poly (ADP-ribose) polymerase-1 deficient mice. EMBO J 18:4446–4454. doi:10.1093/emboj/18.16.4446

    Article  PubMed  CAS  Google Scholar 

  82. Wang D, Westerheide SD, Hanson JL, Baldwin AS Jr (2000) Tumor necrosis factor alpha-induced phosphorylation of RelA/p65 on Ser529 is controlled by casein kinase II. J Biol Chem 275:32592–32597. doi:10.1074/jbc.M001358200

    Article  PubMed  CAS  Google Scholar 

  83. Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M, Shoelson SE (2001) Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science 293:1673–1677. doi:10.1126/science.1061620

    Article  PubMed  CAS  Google Scholar 

  84. Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, Shoelson SE (2005) Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med 11:183–190. doi:10.1038/nm1166

    Article  PubMed  CAS  Google Scholar 

  85. DeAngelis RA, Markiewski MM, Taub R, Lambris JD (2005) A high-fat diet impairs liver regeneration in C57BL/6 mice through overexpression of the NF-kappaB inhibitor, IkappaBalpha. Hepatology 42:1148–1157. doi:10.1002/hep.20879

    Article  PubMed  CAS  Google Scholar 

  86. Beraza N, Malato Y, Vander BS et al (2008) Pharmacological IKK2 inhibition blocks liver steatosis and initiation of non-alcoholic steatohepatitis. Gut 57:655–663. doi:10.1136/gut.2007.134288

    Article  PubMed  CAS  Google Scholar 

  87. Luedde T, Beraza N, Kotsikoris V et al (2007) Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma. Cancer Cell 11:119–132. doi:10.1016/j.ccr.2006.12.016

    Article  PubMed  CAS  Google Scholar 

  88. Budick-Harmelin N, Dudas J, Demuth J, Madar Z, Ramadori G, Tirosh O (2008) Triglycerides potentiate the inflammatory response in rat Kupffer cells. Antioxid Redox Signal 10:2009–2022. doi:10.1089/ars.2007.1876

    Article  PubMed  CAS  Google Scholar 

  89. Tomita K, Tamiya G, Ando S et al (2006) Tumour necrosis factor alpha signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice. Gut 55:415–424. doi:10.1136/gut.2005.071118

    Article  PubMed  CAS  Google Scholar 

  90. Ma X, Hua J, Li Z (2008) Probiotics improve high fat diet-induced hepatic steatosis and insulin resistance by increasing hepatic NKT cells. J Hepatol 49:821–830. doi:10.1016/j.jhep.2008.05.025

    Article  PubMed  CAS  Google Scholar 

  91. Li Z, Soloski MJ, Diehl AM (2005) Dietary factors alter hepatic innate immune system in mice with nonalcoholic fatty liver disease. Hepatology 42:880–885. doi:10.1002/hep.20826

    Article  PubMed  CAS  Google Scholar 

  92. Rasouli N, Kern PA (2008) Adipocytokines and the metabolic complications of obesity. J Clin Endocrinol Metab 93:S64–S73. doi:10.1210/jc.2008-1613

    Article  PubMed  CAS  Google Scholar 

  93. Luedde T, Trautwein C (2006) Intracellular survival pathways in the liver. Liver Int 26:1163–1174. doi:10.1111/j.1478-3231.2006.01366.x

    Article  PubMed  CAS  Google Scholar 

  94. Feng F, Wang L, Albanese N, Holmes A, Xia P (2008) Tumor necrosis factor-like weak inducer of apoptosis attenuates the action of insulin in hepatocytes. Endocrinology 149:1505–1513. doi:10.1210/en.2007-1119

    Article  PubMed  CAS  Google Scholar 

  95. Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444:860–867. doi:10.1038/nature05485

    Article  PubMed  CAS  Google Scholar 

  96. Hirosumi J, Tuncman G, Chang L et al (2002) A central role for JNK in obesity and insulin resistance. Nature 420:333–336. doi:10.1038/nature01137

    Article  PubMed  CAS  Google Scholar 

  97. Schattenberg JM, Singh R, Wang Y, Lefkowitch JH, Rigoli RM, Scherer PE, Czaja MJ (2006) JNK1 but not JNK2 promotes the development of steatohepatitis in mice. Hepatology 43:163–172. doi:10.1002/hep.20999

    Article  PubMed  CAS  Google Scholar 

  98. Sabio G, Das M, Mora A et al (2008) A stress signaling pathway in adipose tissue regulates hepatic insulin resistance. Science 322:1539–1543. doi:10.1126/science.1160794

    Article  PubMed  CAS  Google Scholar 

  99. Davis RJ (2000) Signal transduction by the JNK group of MAP kinases. Cell 103:239–252. doi:10.1016/S0092-8674(00)00116-1

    Article  PubMed  CAS  Google Scholar 

  100. Singh R, Wang Y, Xiang Y, Tanaka KE, Gaarde WA, Czaja MJ (2009) Differential effects of JNK1 and JNK2 inhibition on murine steatohepatitis and insulin resistance. Hepatology 49:87–96. doi:10.1002/hep.22578

    Article  PubMed  CAS  Google Scholar 

  101. Czaja MJ (2007) Cell signaling in oxidative stress-induced liver injury. Semin Liver Dis 27:378–389. doi:10.1055/s-2007-991514

    Article  PubMed  CAS  Google Scholar 

  102. Czaja MJ, Liu H, Wang Y (2003) Oxidant-induced hepatocyte injury from menadione is regulated by ERK and AP-1 signaling. Hepatology 37:1405–1413. doi:10.1053/jhep.2003.50233

    Article  PubMed  CAS  Google Scholar 

  103. Wang Y, Singh R, Lefkowitch JH, Rigoli RM, Czaja MJ (2006) Tumor necrosis factor-induced toxic liver injury results from JNK2-dependent activation of caspase-8 and the mitochondrial death pathway. J Biol Chem 281:15258–15267. doi:10.1074/jbc.M512953200

    Article  PubMed  CAS  Google Scholar 

  104. Alexander WS (2002) Suppressors of cytokine signalling (SOCS) in the immune system. Nat Rev Immunol 2:410–416

    PubMed  CAS  Google Scholar 

  105. Rui L, Yuan M, Frantz D, Shoelson S, White MF (2002) SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. J Biol Chem 277:42394–42398. doi:10.1074/jbc.C200444200

    Article  PubMed  CAS  Google Scholar 

  106. Ueki K, Kondo T, Tseng YH, Kahn CR (2004) Central role of suppressors of cytokine signaling proteins in hepatic steatosis, insulin resistance, and the metabolic syndrome in the mouse. Proc Natl Acad Sci USA 101:10422–10427. doi:10.1073/pnas.0402511101

    Article  PubMed  CAS  Google Scholar 

  107. Emanuelli B, Peraldi P, Filloux C et al (2001) SOCS-3 inhibits insulin signaling and is up-regulated in response to tumor necrosis factor-alpha in the adipose tissue of obese mice. J Biol Chem 276:47944–47949. doi:10.1074/jbc.M104602200

    PubMed  CAS  Google Scholar 

  108. Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Matsubara K (1996) cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (adipose most abundant gene transcript 1). Biochem Biophys Res Commun 221:286–289. doi:10.1006/bbrc.1996.0587

    Article  PubMed  CAS  Google Scholar 

  109. Pajvani UB, Hawkins M, Combs TP et al (2004) Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity. J Biol Chem 279:12152–12162. doi:10.1074/jbc.M311113200

    Article  PubMed  CAS  Google Scholar 

  110. Bluher M, Brennan AM, Kelesidis T et al (2007) Total and high-molecular weight adiponectin in relation to metabolic variables at baseline and in response to an exercise treatment program: comparative evaluation of three assays. Diabetes Care 30:280–285. doi:10.2337/dc06-1362

    Article  PubMed  CAS  Google Scholar 

  111. Berg AH, Combs TP, Du X, Brownlee M, Scherer PE (2001) The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med 7:947–953. doi:10.1038/90992

    Article  PubMed  CAS  Google Scholar 

  112. Karbowska J, Kochan Z (2006) Role of adiponectin in the regulation of carbohydrate and lipid metabolism. J Physiol Pharmacol 57(Suppl 6):103–113

    PubMed  Google Scholar 

  113. Minokoshi Y, Shiuchi T, Lee S, Suzuki A, Okamoto S (2008) Role of hypothalamic AMP-kinase in food intake regulation. Nutrition 24:786–790. doi:10.1016/j.nut.2008.06.002

    Article  PubMed  CAS  Google Scholar 

  114. Maeda N, Shimomura I, Kishida K et al (2002) Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med 8:731–737. doi:10.1038/nm724

    Article  PubMed  CAS  Google Scholar 

  115. Kubota N, Terauchi Y, Yamauchi T et al (2002) Disruption of adiponectin causes insulin resistance and neointimal formation. J Biol Chem 277:25863–25866. doi:10.1074/jbc.C200251200

    Article  PubMed  CAS  Google Scholar 

  116. Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J (2004) Beyond insulin resistance in NASH: TNF-alpha or adiponectin? Hepatology 40:46–54. doi:10.1002/hep.20280

    Article  PubMed  CAS  Google Scholar 

  117. Menzaghi C, Trischitta V, Doria A (2007) Genetic influences of adiponectin on insulin resistance, type 2 diabetes, and cardiovascular disease. Diabetes 56:1198–1209. doi:10.2337/db06-0506

    Article  PubMed  CAS  Google Scholar 

  118. Gilardini L, McTernan PG, Girola A, da Silva NF, Alberti L, Kumar S, Invitti C (2006) Adiponectin is a candidate marker of metabolic syndrome in obese children and adolescents. Atherosclerosis 189:401–407. doi:10.1016/j.atherosclerosis.2005.12.021

    Article  PubMed  CAS  Google Scholar 

  119. Yamauchi T, Kamon J, Ito Y et al (2003) Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 423:762–769. doi:10.1038/nature01705

    Article  PubMed  CAS  Google Scholar 

  120. Yamauchi T, Nio Y, Maki T et al (2007) Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat Med 13:332–339. doi:10.1038/nm1557

    Article  PubMed  CAS  Google Scholar 

  121. Fruebis J, Tsao TS, Javorschi S et al (2001) Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci USA 98:2005–2010. doi:10.1073/pnas.041591798

    Article  PubMed  CAS  Google Scholar 

  122. Musso G, Gambino R, Biroli G et al (2005) Hypoadiponectinemia predicts the severity of hepatic fibrosis and pancreatic beta-cell dysfunction in nondiabetic nonobese patients with nonalcoholic steatohepatitis. Am J Gastroenterol 100:2438–2446. doi:10.1111/j.1572-0241.2005.00297.x

    Article  PubMed  CAS  Google Scholar 

  123. Devaraj S, Torok N, Dasu MR, Samols D, Jialal I (2008) Adiponectin decreases C-reactive protein synthesis and secretion from endothelial cells: evidence for an adipose tissue-vascular loop. Arterioscler Thromb Vasc Biol 28:1368–1374. doi:10.1161/ATVBAHA.108.163303

    Article  PubMed  CAS  Google Scholar 

  124. Masaki T, Chiba S, Tatsukawa H, Yasuda T, Noguchi H, Seike M, Yoshimatsu H (2004) Adiponectin protects LPS-induced liver injury through modulation of TNF-alpha in KK-Ay obese mice. Hepatology 40:177–184. doi:10.1002/hep.20282

    Article  PubMed  CAS  Google Scholar 

  125. Xu A, Wang Y, Keshaw H, Xu LY, Lam KS, Cooper GJ (2003) The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest 112:91–100. doi:10.1172/JCI17797

    PubMed  CAS  Google Scholar 

  126. Ouedraogo R, Gong Y, Berzins B et al (2007) Adiponectin deficiency increases leukocyte-endothelium interactions via upregulation of endothelial cell adhesion molecules in vivo. J Clin Invest 117:1718–1726. doi:10.1172/JCI29623

    Article  PubMed  CAS  Google Scholar 

  127. Matsumoto H, Tamura S, Kamada Y et al (2006) Adiponectin deficiency exacerbates lipopolysaccharide/D-galactosamine-induced liver injury in mice. World J Gastroenterol 12:3352–3358

    PubMed  CAS  Google Scholar 

  128. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432. doi:10.1038/372425a0

    Article  PubMed  CAS  Google Scholar 

  129. Friedman JM (2009) Leptin at 14 y of age: an ongoing story. Am J Clin Nutr 89:973S–979S. doi:10.3945/ajcn.2008.26788B

    Article  PubMed  CAS  Google Scholar 

  130. Begriche K, Letteron P, Abbey-Toby A et al (2008) Partial leptin deficiency favors diet-induced obesity and related metabolic disorders in mice. Am J Physiol Endocrinol Metab 294:E939–E951. doi:10.1152/ajpendo.00379.2007

    Article  PubMed  CAS  Google Scholar 

  131. Zhang Y, Scarpace PJ (2006) The role of leptin in leptin resistance and obesity. Physiol Behav 88:249–256. doi:10.1016/j.physbeh.2006.05.038

    Article  PubMed  CAS  Google Scholar 

  132. Badman MK, Flier JS (2007) The adipocyte as an active participant in energy balance and metabolism. Gastroenterology 132:2103–2115. doi:10.1053/j.gastro.2007.03.058

    Article  PubMed  CAS  Google Scholar 

  133. Li Z, Lin H, Yang S, Diehl AM (2002) Murine leptin deficiency alters Kupffer cell production of cytokines that regulate the innate immune system. Gastroenterology 123:1304–1310. doi:10.1053/gast.2002.35997

    Article  PubMed  CAS  Google Scholar 

  134. Sennello JA, Fayad R, Pini M, Gove ME, Fantuzzi G (2006) Transplantation of wild-type white adipose tissue normalizes metabolic, immune and inflammatory alterations in leptin-deficient ob/ob mice. Cytokine 36:261–266. doi:10.1016/j.cyto.2007.02.001

    Article  PubMed  CAS  Google Scholar 

  135. Sandhofer A, Laimer M, Ebenbichler CF, Kaser S, Paulweber B, Patsch JR (2003) Soluble leptin receptor and soluble receptor-bound fraction of leptin in the metabolic syndrome. Obes Res 11:760–768. doi:10.1038/oby.2003.106

    Article  PubMed  CAS  Google Scholar 

  136. Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D, Kahn BB (2002) Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 415:339–343. doi:10.1038/415339a

    Article  PubMed  CAS  Google Scholar 

  137. Brabant G, Muller G, Horn R, Anderwald C, Roden M, Nave H (2005) Hepatic leptin signaling in obesity. FASEB J 19:1048–1050. doi:10.1096/fj.04-2846fje

    PubMed  CAS  Google Scholar 

  138. Kakuma T, Lee Y, Higa M, Wang Z, Pan W, Shimomura I, Unger RH (2000) Leptin, troglitazone, and the expression of sterol regulatory element binding proteins in liver and pancreatic islets. Proc Natl Acad Sci USA 97:8536–8541. doi:10.1073/pnas.97.15.8536

    Article  PubMed  CAS  Google Scholar 

  139. Feldstein AE, Canbay A, Guicciardi ME, Higuchi H, Bronk SF, Gores GJ (2003) Diet associated hepatic steatosis sensitizes to Fas mediated liver injury in mice. J Hepatol 39:978–983. doi:10.1016/S0168-8278(03)00460-4

    Article  PubMed  CAS  Google Scholar 

  140. Ikejima K, Honda H, Yoshikawa M, Hirose M, Kitamura T, Takei Y, Sato N (2001) Leptin augments inflammatory and profibrogenic responses in the murine liver induced by hepatotoxic chemicals. Hepatology 34:288–297. doi:10.1053/jhep.2001.26518

    Article  PubMed  CAS  Google Scholar 

  141. Saxena NK, Titus MA, Ding X, Floyd J, Srinivasan S, Sitaraman SV, Anania FA (2004) Leptin as a novel profibrogenic cytokine in hepatic stellate cells: mitogenesis and inhibition of apoptosis mediated by extracellular regulated kinase (Erk) and Akt phosphorylation. FASEB J 18:1612–1614. doi:10.1096/fj.04-1847fje

    PubMed  CAS  Google Scholar 

  142. Cao Q, Mak KM, Ren C, Lieber CS (2004) Leptin stimulates tissue inhibitor of metalloproteinase-1 in human hepatic stellate cells: respective roles of the JAK/STAT and JAK-mediated H2O2-dependant MAPK pathways. J Biol Chem 279:4292–4304. doi:10.1074/jbc.M308351200

    Article  PubMed  CAS  Google Scholar 

  143. Testa R, Franceschini R, Giannini E et al (2000) Serum leptin levels in patients with viral chronic hepatitis or liver cirrhosis. J Hepatol 33:33–37. doi:10.1016/S0168-8278(00)80156-7

    Article  PubMed  CAS  Google Scholar 

  144. Chitturi S, Farrell G, Frost L et al (2002) Serum leptin in NASH correlates with hepatic steatosis but not fibrosis: a manifestation of lipotoxicity? Hepatology 36:403–409. doi:10.1053/jhep.2002.34738

    Article  PubMed  CAS  Google Scholar 

  145. Banerjee RR, Rangwala SM, Shapiro JS et al (2004) Regulation of fasted blood glucose by resistin. Science 303:1195–1198. doi:10.1126/science.1092341

    Article  PubMed  CAS  Google Scholar 

  146. Sato N, Kobayashi K, Inoguchi T et al (2005) Adenovirus-mediated high expression of resistin causes dyslipidemia in mice. Endocrinology 146:273–279. doi:10.1210/en.2004-0985

    Article  PubMed  CAS  Google Scholar 

  147. Yang Y, Xiao M, Mao Y, et al (2008) Resistin and insulin resistance in hepatocytes: resistin disturbs glycogen metabolism at the protein level. Biomed Pharmacother 63:366–374. doi:10.1016/j.biopha.2008.06.033

    Google Scholar 

  148. Palanivel R, Maida A, Liu Y, Sweeney G (2006) Regulation of insulin signalling, glucose uptake and metabolism in rat skeletal muscle cells upon prolonged exposure to resistin. Diabetologia 49:183–190. doi:10.1007/s00125-005-0060-z

    Article  PubMed  CAS  Google Scholar 

  149. Kitagawa Y, Bujo H, Takahashi K et al (2004) Impaired glucose tolerance is accompanied by decreased insulin sensitivity in tissues of mice implanted with cells that overexpress resistin. Diabetologia 47:1847–1853. doi:10.1007/s00125-004-1530-4

    Article  PubMed  CAS  Google Scholar 

  150. Tetri LH, Basaranoglu M, Brunt EM, Yerian LM, Neuschwander-Tetri BA (2008) Severe NAFLD with hepatic necroinflammatory changes in mice fed trans fats and a high-fructose corn syrup equivalent. Am J Physiol Gastrointest Liver Physiol 295:G987–G995. doi:10.1152/ajpgi.90272.2008

    Article  PubMed  CAS  Google Scholar 

  151. Pagano C, Soardo G, Pilon C et al (2006) Increased serum resistin in nonalcoholic fatty liver disease is related to liver disease severity and not to insulin resistance. J Clin Endocrinol Metab 91:1081–1086. doi:10.1210/jc.2005-1056

    Article  PubMed  CAS  Google Scholar 

  152. Bertolani C, Sancho-Bru P, Failli P et al (2006) Resistin as an intrahepatic cytokine: overexpression during chronic injury and induction of proinflammatory actions in hepatic stellate cells. Am J Pathol 169:2042–2053. doi:10.2353/ajpath.2006.060081

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. I. Medizinsiche Klinik, University Medical Center of the Johannes Gutenberg University, Langenbeckstrasse 1, 55131, Mainz, Germany

    Jörn M. Schattenberg & Marcus Schuchmann

Authors
  1. Jörn M. Schattenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marcus Schuchmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jörn M. Schattenberg.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schattenberg, J.M., Schuchmann, M. Diabetes and apoptosis: liver. Apoptosis 14, 1459–1471 (2009). https://doi.org/10.1007/s10495-009-0366-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-009-0366-2

Keywords

Search

Navigation