KEGG   PATHWAY: ko04932
ko04932                     Pathway                                
Non-alcoholic fatty liver disease
Non-alcoholic fatty liver disease (NAFLD) represents a spectrum ranging from simple steatosis to more severe steatohepatitis with hepatic inflammation and fibrosis, known as nonalcoholic steatohepatitis (NASH). NASH may further lead to cirrhosis and hepatocellular carcinoma (HCC). This map shows a stage-dependent progression of NAFLD. In the first stage of NAFLD, excess lipid accumulation has been demonstrated. The main cause is the induction of insulin resistance, which leads to a defect in insulin suppression of free fatty acids (FAAs) disposal. In addition, two transcription factors, SREBP-1c and PPAR-alpha, activate key enzymes of lipogenesis and increase the synthesis of FAAs in liver. In the second stage, as a consequence of the progression to NASH, the production of reactive oxygen species (ROS) is enhanced due to oxidation stress through mitochondrial beta-oxidation of fatty acids and endoplamic reticulum (ER) stress, leading to lipid peroxidation. The lipid peroxidation can further cause the production of cytokines (Fas ligand, TNF-alpha, IL-8 and TGF), promoting cell death, inflammation and fibrosis. The activation of JNK, which is induced by ER stress, TNF-alpha and FAAs, is also associated with NAFLD progression. Increased JNK promotes cytokine production and initiation of HCC.
Human Diseases; Endocrine and metabolic disease
Pathway map
ko04932  Non-alcoholic fatty liver disease

H01333  Non-alcoholic fatty liver disease
K05405  interleukin 6
K05055  interleukin 6 receptor
K04696  suppressor of cytokine signaling 3
K03156  tumor necrosis factor superfamily, member 2
K03158  tumor necrosis factor receptor superfamily member 1A
K02580  nuclear factor NF-kappa-B p105 subunit
K04735  transcription factor p65
K04526  insulin
K04527  insulin receptor [EC:]
K16172  insulin receptor substrate 1
K07187  insulin receptor substrate 2
K00922  phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:]
K02649  phosphoinositide-3-kinase regulatory subunit alpha/beta/delta
K04456  RAC serine/threonine-protein kinase [EC:]
K08822  glycogen synthase kinase 3 alpha [EC:]
K03083  glycogen synthase kinase 3 beta [EC:]
K08536  liver X receptor alpha
K08524  retinoid X receptor alpha
K07197  sterol regulatory element-binding transcription factor 1
K09113  MAX-like protein X
K12406  pyruvate kinase isozymes R/L [EC:]
K05424  leptin
K05062  leptin receptor
K07296  adiponectin
K07297  adiponectin receptor
K07198  5'-AMP-activated protein kinase, catalytic alpha subunit [EC:]
K07199  5'-AMP-activated protein kinase, regulatory beta subunit
K07200  5'-AMP-activated protein kinase, regulatory gamma subunit
K04441  p38 MAP kinase [EC:]
K07294  peroxisome proliferator-activated receptor alpha
K08530  peroxisome proliferator-activated receptor gamma
K04393  cell division control protein 42
K04392  Ras-related C3 botulinum toxin substrate 1
K04419  mitogen-activated protein kinase kinase kinase 11 [EC:]
K04440  mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:]
K05632  E3 ubiquitin-protein ligase Itchy [EC:]
K08852  serine/threonine-protein kinase/endoribonuclease IRE1 [EC: 3.1.26.-]
K03173  TNF receptor-associated factor 2 [EC:]
K04426  mitogen-activated protein kinase kinase kinase 5 [EC:]
K04379  proto-oncogene protein c-fos
K04448  transcription factor AP-1
K04383  interleukin 1 alpha
K04519  interleukin 1 beta
K07209  inhibitor of nuclear factor kappa-B kinase subunit beta [EC:]
K09027  X box-binding protein 1
K09055  CCAAT/enhancer binding protein (C/EBP), alpha
K07415  cytochrome P450 family 2 subfamily E1 [EC:1.14.14.-]
K04389  tumor necrosis factor ligand superfamily member 6
K10030  interleukin 8
K13375  transforming growth factor beta-1
K08860  eukaryotic translation initiation factor 2-alpha kinase 3 [EC:]
K03237  translation initiation factor 2 subunit 1
K04374  cyclic AMP-dependent transcription factor ATF-4
K04452  DNA damage-inducible transcript 3
K16341  Bcl-2-like protein 11
K02159  apoptosis regulator BAX
K04390  tumor necrosis factor receptor superfamily member 6
K04398  caspase 8 [EC:]
K04726  BH3 interacting domain death agonist
K08738  cytochrome c
K02187  caspase 3 [EC:]
K04397  caspase 7 [EC:]
K03942  NADH dehydrogenase (ubiquinone) flavoprotein 1 [EC:]
K03943  NADH dehydrogenase (ubiquinone) flavoprotein 2 [EC:]
K03944  NADH dehydrogenase (ubiquinone) flavoprotein 3
K03945  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 1
K03946  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 2
K03947  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 3
K03948  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 4
K03949  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 5
K03950  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 6
K03951  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 7
K03952  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 8
K03953  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 9
K03954  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 10
K03955  NADH dehydrogenase (ubiquinone) 1 alpha/beta subcomplex 1, acyl-carrier protein
K03956  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 11
K11352  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 12
K11353  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 13
K03957  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 1
K03958  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 2
K03959  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 3
K03960  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 4
K03961  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 5
K03962  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 6
K03963  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 7
K03964  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 8
K03965  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 9
K03966  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 10
K11351  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 11
K03934  NADH dehydrogenase (ubiquinone) Fe-S protein 1 [EC:]
K03935  NADH dehydrogenase (ubiquinone) Fe-S protein 2 [EC:]
K03936  NADH dehydrogenase (ubiquinone) Fe-S protein 3 [EC:]
K03937  NADH dehydrogenase (ubiquinone) Fe-S protein 4
K03938  NADH dehydrogenase (ubiquinone) Fe-S protein 5
K03939  NADH dehydrogenase (ubiquinone) Fe-S protein 6
K03940  NADH dehydrogenase (ubiquinone) Fe-S protein 7 [EC:]
K03941  NADH dehydrogenase (ubiquinone) Fe-S protein 8 [EC:]
K03967  NADH dehydrogenase (ubiquinone) 1 subunit C1
K03968  NADH dehydrogenase (ubiquinone) 1 subunit C2
K00234  succinate dehydrogenase (ubiquinone) flavoprotein subunit [EC:]
K00235  succinate dehydrogenase (ubiquinone) iron-sulfur subunit [EC:]
K00236  succinate dehydrogenase (ubiquinone) cytochrome b560 subunit
K00237  succinate dehydrogenase (ubiquinone) membrane anchor subunit
K00411  ubiquinol-cytochrome c reductase iron-sulfur subunit [EC:]
K00412  ubiquinol-cytochrome c reductase cytochrome b subunit
K00413  ubiquinol-cytochrome c reductase cytochrome c1 subunit
K00414  ubiquinol-cytochrome c reductase core subunit 1
K00415  ubiquinol-cytochrome c reductase core subunit 2
K00416  ubiquinol-cytochrome c reductase subunit 6
K00417  ubiquinol-cytochrome c reductase subunit 7
K00418  ubiquinol-cytochrome c reductase subunit 8
K00419  ubiquinol-cytochrome c reductase subunit 9
K00420  ubiquinol-cytochrome c reductase subunit 10
K02262  cytochrome c oxidase subunit 3
K02256  cytochrome c oxidase subunit 1 [EC:]
K02261  cytochrome c oxidase subunit 2
K02263  cytochrome c oxidase subunit 4
K02264  cytochrome c oxidase subunit 5a
K02265  cytochrome c oxidase subunit 5b
K02266  cytochrome c oxidase subunit 6a
K02267  cytochrome c oxidase subunit 6b
K02268  cytochrome c oxidase subunit 6c
K02270  cytochrome c oxidase subunit 7a
K02271  cytochrome c oxidase subunit 7b
K02272  cytochrome c oxidase subunit 7c
K02273  cytochrome c oxidase subunit 8
C00031  D-Glucose
C00162  Fatty acid
Naik A, Kosir R, Rozman D
Genomic aspects of NAFLD pathogenesis.
Genomics 102:84-95 (2013)
Malaguarnera M, Di Rosa M, Nicoletti F, Malaguarnera L
Molecular mechanisms involved in NAFLD progression.
J Mol Med (Berl) 87:679-95 (2009)
Seki E, Brenner DA, Karin M
A liver full of JNK: signaling in regulation of cell function and disease pathogenesis, and clinical approaches.
Gastroenterology 143:307-20 (2012)
Tilg H, Moschen AR
Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis.
Hepatology 52:1836-46 (2010)
Larter CZ, Farrell GC
Insulin resistance, adiponectin, cytokines in NASH: Which is the best target to treat?
J Hepatol 44:253-61 (2006)
Farrell GC, van Rooyen D, Gan L, Chitturi S
NASH is an Inflammatory Disorder: Pathogenic, Prognostic and Therapeutic Implications.
Gut Liver 6:149-71 (2012)
Shapiro H, Tehilla M, Attal-Singer J, Bruck R, Luzzatti R, Singer P
The therapeutic potential of long-chain omega-3 fatty acids in nonalcoholic fatty liver disease.
Clin Nutr 30:6-19 (2011)
Hotamisligil GS
Endoplasmic reticulum stress and the inflammatory basis of metabolic disease.
Cell 140:900-17 (2010)
Parekh S, Anania FA
Abnormal lipid and glucose metabolism in obesity: implications for nonalcoholic fatty liver disease.
Gastroenterology 132:2191-207 (2007)
Schattenberg JM, Singh R, Wang Y, Lefkowitch JH, Rigoli RM, Scherer PE, Czaja MJ
JNK1 but not JNK2 promotes the development of steatohepatitis in mice.
Hepatology 43:163-72 (2006)
Leung TM, Nieto N
CYP2E1 and oxidant stress in alcoholic and non-alcoholic fatty liver disease.
J Hepatol 58:395-8 (2013)
Zafrani ES
Non-alcoholic fatty liver disease: an emerging pathological spectrum.
Virchows Arch 444:3-12 (2004)
Feldstein AE, Canbay A, Angulo P, Taniai M, Burgart LJ, Lindor KD, Gores GJ
Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis.
Gastroenterology 125:437-43 (2003)
Begriche K, Igoudjil A, Pessayre D, Fromenty B
Mitochondrial dysfunction in NASH: causes, consequences and possible means to prevent it.
Mitochondrion 6:1-28 (2006)
Leonarduzzi G, Scavazza A, Biasi F, Chiarpotto E, Camandola S, Vogel S, Dargel R, Poli G
The lipid peroxidation end product 4-hydroxy-2,3-nonenal up-regulates transforming growth factor beta1 expression in the macrophage lineage: a link between oxidative injury and fibrosclerosis.
FASEB J 11:851-7 (1997)
Malhi H, Kaufman RJ
Endoplasmic reticulum stress in liver disease.
J Hepatol 54:795-809 (2011)
Mantena SK, King AL, Andringa KK, Eccleston HB, Bailey SM
Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases.
Free Radic Biol Med 44:1259-72 (2008)
Serviddio G, Sastre J, Bellanti F, Vina J, Vendemiale G, Altomare E
Mitochondrial involvement in non-alcoholic steatohepatitis.
Mol Aspects Med 29:22-35 (2008)
Begriche K, Massart J, Robin MA, Bonnet F, Fromenty B
Mitochondrial adaptations and dysfunctions in nonalcoholic fatty liver disease.
Hepatology 58:1497-507 (2013)
ko00061  Fatty acid biosynthesis
ko00190  Oxidative phosphorylation
ko03320  PPAR signaling pathway
ko04141  Protein processing in endoplasmic reticulum
ko04151  PI3K-Akt signaling pathway
ko04210  Apoptosis
ko04668  TNF signaling pathway
ko04920  Adipocytokine signaling pathway
ko04930  Type II diabetes mellitus

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