KEGG   PATHWAY: nvs04932
Entry
nvs04932                    Pathway                                
Name
Non-alcoholic fatty liver disease - Neogale vison (American mink)
Description
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.
Class
Human Diseases; Endocrine and metabolic disease
Pathway map
nvs04932  Non-alcoholic fatty liver disease
nvs04932

Disease
H01333  Non-alcoholic fatty liver disease
Organism
Neogale vison (American mink) [GN:nvs]
Gene
122889094  [KO:K04726]
122889330  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
122889452  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
122889565  [KO:K00417]
122889784  [KO:K02271]
122889856  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
122889942  [KO:K00418]
122889990  CASP3; caspase-3 [KO:K02187] [EC:3.4.22.56]
122890557  NDUFA2; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 2 [KO:K03946]
122891108  NDUFA9; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9, mitochondrial [KO:K03953]
122891254  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
122891482  NDUFA4L2; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 4-like 2 [KO:K03948]
122891540  BID; BH3-interacting domain death agonist [KO:K04726]
122891747  NDUFA12; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 12 [KO:K11352]
122891839  [KO:K00418]
122891864  NDUFA6; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 6 [KO:K03950]
122891883  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
122891909  MAPK12; mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
122891975  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
122891980  [KO:K02267]
122892035  PPARA; peroxisome proliferator-activated receptor alpha [KO:K07294]
122892060  ADIPOR2; adiponectin receptor protein 2 isoform X1 [KO:K07297]
122892438  [KO:K00417]
122892467  [KO:K03967]
122892505  TNFRSF1A; tumor necrosis factor receptor superfamily member 1A [KO:K03158]
122892516  DDIT3; DNA damage-inducible transcript 3 protein [KO:K04452]
122893478  FOS; proto-oncogene c-Fos [KO:K04379]
122893690  [KO:K02264]
122893967  EIF2S1; eukaryotic translation initiation factor 2 subunit 1 [KO:K03237]
122894172  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
122894239  [KO:K02266]
122894329  NDUFS4; NADH dehydrogenase [ubiquinone] iron-sulfur protein 4, mitochondrial [KO:K03937]
122894479  NDUFB1; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 1 [KO:K03957]
122894691  [KO:K03948]
122894750  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
122895433  [KO:K02266]
122895608  NDUFAB1; acyl carrier protein, mitochondrial [KO:K03955]
122895793  [KO:K00415]
122895803  MLXIPL; carbohydrate-responsive element-binding protein isoform X1 [KO:K09113]
122895963  RAC1; ras-related C3 botulinum toxin substrate 1 isoform X1 [KO:K04392]
122896017  [KO:K09027]
122896151  NDUFS6; NADH dehydrogenase [ubiquinone] iron-sulfur protein 6, mitochondrial isoform X1 [KO:K03939]
122896181  NDUFB10; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 10 [KO:K03966]
122896387  SDHA; succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial isoform X1 [KO:K00234] [EC:1.3.5.1]
122896390  [KO:K02268]
122897039  [KO:K03938]
122897149  NDUFA1; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1 [KO:K03945]
122897159  [KO:K02271]
122897372  [KO:K03948]
122897479  [KO:K02272]
122897493  [KO:K02270]
122897625  NDUFB11; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 11, mitochondrial [KO:K11351]
122899062  [KO:K07415] [EC:1.14.14.-]
122899425  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
122899501  SDHB; succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial [KO:K00235] [EC:1.3.5.1]
122899548  CDC42; cell division control protein 42 homolog isoform X1 [KO:K04393]
122899787  NDUFS5; NADH dehydrogenase [ubiquinone] iron-sulfur protein 5 [KO:K03938]
122899916  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
122899923  [KO:K00416]
122899945  TNF; tumor necrosis factor isoform X1 [KO:K03156]
122899957  [KO:K00417]
122900018  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
122900023  JUN; transcription factor AP-1 [KO:K04448]
122900056  LEPR; leptin receptor isoform X1 [KO:K05062]
122900125  [KO:K02271]
122900404  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
122900656  FAS; tumor necrosis factor receptor superfamily member 6 [KO:K04390]
122900866  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
122901022  NDUFB8; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 8, mitochondrial [KO:K03964]
122901125  CASP7; caspase-7 isoform X1 [KO:K04397] [EC:3.4.22.60]
122901740  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
122901810  [KO:K04393]
122902031  [KO:K00419]
122902186  NDUFB3; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 3 [KO:K03959]
122902190  CASP8; caspase-8 isoform X1 [KO:K04398] [EC:3.4.22.61]
122902230  NDUFS1; NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial [KO:K03934] [EC:7.1.1.2]
122902369  IRS1; insulin receptor substrate 1 [KO:K16172]
122902465  NDUFA10; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10, mitochondrial [KO:K03954]
122902631  [KO:K08738]
122902991  [KO:K08738]
122903016  [KO:K03967]
122903032  NDUFV2; NADH dehydrogenase [ubiquinone] flavoprotein 2, mitochondrial [KO:K03943] [EC:7.1.1.2]
122903049  [KO:K09113]
122903290  XBP1; LOW QUALITY PROTEIN: X-box-binding protein 1 [KO:K09027]
122903357  [KO:K02266]
122903371  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
122903450  [KO:K02270]
122903641  [KO:K03948]
122904064  IL6; interleukin-6 [KO:K05405]
122904118  [KO:K05424]
122904230  [KO:K00413]
122904311  NDUFB9; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 9 [KO:K03965]
122904422  [KO:K00417]
122904860  NDUFA4; cytochrome c oxidase subunit NDUFA4 [KO:K03948]
122904917  [KO:K08738]
122905031  NDUFA5; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 5 [KO:K03949]
122905137  NDUFB2; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 2, mitochondrial [KO:K03958]
122905216  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
122905394  [KO:K02270]
122905934  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
122906080  ERN1; serine/threonine-protein kinase/endoribonuclease IRE1 [KO:K08852] [EC:2.7.11.1 3.1.26.-]
122906190  MLX; max-like protein X isoform X1 [KO:K09113]
122906214  [KO:K03938]
122906270  MAP3K5; mitogen-activated protein kinase kinase kinase 5 isoform X1 [KO:K04426] [EC:2.7.11.25]
122906856  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
122907240  IRS2; insulin receptor substrate 2 [KO:K07187]
122908267  NDUFV3; NADH dehydrogenase [ubiquinone] flavoprotein 3, mitochondrial isoform X1 [KO:K03944]
122908538  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
122908543  NDUFB4; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 4 [KO:K03960]
122908712  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
122908719  NDUFB5; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 5, mitochondrial isoform X1 [KO:K03961]
122908788  ADIPOQ; adiponectin [KO:K07296]
122908823  [KO:K03938]
122908899  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
122909195  PPARG; peroxisome proliferator-activated receptor gamma isoform X1 [KO:K08530]
122909454  [KO:K00414]
122909517  NDUFA13; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 13 [KO:K11353]
122909545  NDUFB7; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 7 [KO:K03963]
122909588  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
122909778  INSR; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
122909800  [KO:K03960]
122909803  NDUFA7; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 7 [KO:K03951]
122909833  NDUFA11; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 11 [KO:K03956]
122909942  [KO:K00420]
122909951  NDUFS7; NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial [KO:K03940] [EC:7.1.1.2]
122910054  [KO:K00236]
122910059  [KO:K02272]
122910068  MAPK13; mitogen-activated protein kinase 13 isoform X1 [KO:K04441] [EC:2.7.11.24]
122910086  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
122910115  [KO:K00411] [EC:7.1.1.8]
122911162  [KO:K02263]
122911488  [KO:K00411] [EC:7.1.1.8]
122911517  CEBPA; CCAAT/enhancer-binding protein alpha [KO:K09055]
122911559  [KO:K02267]
122911585  [KO:K02270]
122911678  NDUFA3; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 3 [KO:K03947]
122911843  BAX; apoptosis regulator BAX [KO:K02159]
122912016  GSK3A; glycogen synthase kinase-3 alpha [KO:K08822] [EC:2.7.11.26]
122912036  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
122912064  TGFB1; transforming growth factor beta-1 proprotein isoform X1 [KO:K13375]
122912281  SDHD; succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial isoform X1 [KO:K00237]
122912547  NDUFC2; NADH dehydrogenase [ubiquinone] 1 subunit C2 [KO:K03968]
122912869  [KO:K02267]
122912893  NR1H3; oxysterols receptor LXR-alpha isoform X1 [KO:K08536]
122912907  NDUFS3; NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial [KO:K03936] [EC:7.1.1.2]
122913120  MAP3K11; mitogen-activated protein kinase kinase kinase 11 [KO:K04419] [EC:2.7.11.25]
122913121  RELA; transcription factor p65 [KO:K04735]
122913194  NDUFV1; NADH dehydrogenase [ubiquinone] flavoprotein 1, mitochondrial [KO:K03942] [EC:7.1.1.2]
122913199  NDUFS8; NADH dehydrogenase [ubiquinone] iron-sulfur protein 8, mitochondrial isoform X1 [KO:K03941] [EC:7.1.1.2]
122913938  [KO:K02267]
122914073  [KO:K02268]
122914556  [KO:K02273]
122914590  INS; insulin [KO:K04526]
122915073  EIF2AK3; eukaryotic translation initiation factor 2-alpha kinase 3 [KO:K08860] [EC:2.7.11.1]
122915099  BCL2L11; bcl-2-like protein 11 isoform X1 [KO:K16341]
122915125  [KO:K02270]
122915592  [KO:K03945]
122915598  [KO:K02263]
122915651  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
122915687  [KO:K02265]
122915760  IL1B; interleukin-1 beta [KO:K04519]
122915761  IL1A; interleukin-1 alpha [KO:K04383]
122916145  ITCH; E3 ubiquitin-protein ligase Itchy homolog isoform X1 [KO:K05632] [EC:2.3.2.26]
122917083  TRAF2; TNF receptor-associated factor 2 isoform X1 [KO:K03173] [EC:2.3.2.27]
122917108  RXRA; retinoic acid receptor RXR-alpha isoform X1 [KO:K08524]
122917290  NDUFA8; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 8 [KO:K03952]
122917534  NDUFB6; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 6 [KO:K03962]
122917769  [KO:K02272]
122918121  FASLG; tumor necrosis factor ligand superfamily member 6 [KO:K04389]
122918234  IL6R; interleukin-6 receptor subunit alpha isoform X1 [KO:K05055]
122918258  PKLR; pyruvate kinase PKLR isoform X1 [KO:K12406] [EC:2.7.1.40]
122918373  NDUFS2; NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, mitochondrial isoform X1 [KO:K03935] [EC:7.1.1.2]
122918379  SDHC; succinate dehydrogenase cytochrome b560 subunit, mitochondrial [KO:K00236]
122918524  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
122918804  ADIPOR1; adiponectin receptor protein 1 [KO:K07297]
122918946  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
122919183  NDUFC1; NADH dehydrogenase [ubiquinone] 1 subunit C1, mitochondrial [KO:K03967]
122919291  CXCL8; interleukin-8 [KO:K10030]
14841841  COX1; cytochrome c oxidase subunit I [KO:K02256] [EC:7.1.1.9]
14841842  COX2; cytochrome c oxidase subunit II [KO:K02261]
14841845  COX3; cytochrome c oxidase subunit III [KO:K02262]
14841851  CYTB; cytochrome b [KO:K00412]
Compound
C00031  D-Glucose
C00162  Fatty acid
Reference
PMID:23545492
  Authors
Naik A, Kosir R, Rozman D
  Title
Genomic aspects of NAFLD pathogenesis.
  Journal
Genomics 102:84-95 (2013)
DOI:10.1016/j.ygeno.2013.03.007
Reference
PMID:19352614
  Authors
Malaguarnera M, Di Rosa M, Nicoletti F, Malaguarnera L
  Title
Molecular mechanisms involved in NAFLD progression.
  Journal
J Mol Med (Berl) 87:679-95 (2009)
DOI:10.1007/s00109-009-0464-1
Reference
PMID:22705006
  Authors
Seki E, Brenner DA, Karin M
  Title
A liver full of JNK: signaling in regulation of cell function and disease pathogenesis, and clinical approaches.
  Journal
Gastroenterology 143:307-20 (2012)
DOI:10.1053/j.gastro.2012.06.004
Reference
PMID:21038418
  Authors
Tilg H, Moschen AR
  Title
Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis.
  Journal
Hepatology 52:1836-46 (2010)
DOI:10.1002/hep.24001
Reference
PMID:16364488
  Authors
Larter CZ, Farrell GC
  Title
Insulin resistance, adiponectin, cytokines in NASH: Which is the best target to treat?
  Journal
J Hepatol 44:253-61 (2006)
DOI:10.1016/j.jhep.2005.11.030
Reference
PMID:22570745
  Authors
Farrell GC, van Rooyen D, Gan L, Chitturi S
  Title
NASH is an Inflammatory Disorder: Pathogenic, Prognostic and Therapeutic Implications.
  Journal
Gut Liver 6:149-71 (2012)
DOI:10.5009/gnl.2012.6.2.149
Reference
PMID:20619513
  Authors
Shapiro H, Tehilla M, Attal-Singer J, Bruck R, Luzzatti R, Singer P
  Title
The therapeutic potential of long-chain omega-3 fatty acids in nonalcoholic fatty liver disease.
  Journal
Clin Nutr 30:6-19 (2011)
DOI:10.1016/j.clnu.2010.06.001
Reference
PMID:20303879
  Authors
Hotamisligil GS
  Title
Endoplasmic reticulum stress and the inflammatory basis of metabolic disease.
  Journal
Cell 140:900-17 (2010)
DOI:10.1016/j.cell.2010.02.034
Reference
PMID:17498512
  Authors
Parekh S, Anania FA
  Title
Abnormal lipid and glucose metabolism in obesity: implications for nonalcoholic fatty liver disease.
  Journal
Gastroenterology 132:2191-207 (2007)
DOI:10.1053/j.gastro.2007.03.055
Reference
PMID:16374858
  Authors
Schattenberg JM, Singh R, Wang Y, Lefkowitch JH, Rigoli RM, Scherer PE, Czaja MJ
  Title
JNK1 but not JNK2 promotes the development of steatohepatitis in mice.
  Journal
Hepatology 43:163-72 (2006)
DOI:10.1002/hep.20999
Reference
PMID:22940046
  Authors
Leung TM, Nieto N
  Title
CYP2E1 and oxidant stress in alcoholic and non-alcoholic fatty liver disease.
  Journal
J Hepatol 58:395-8 (2013)
DOI:10.1016/j.jhep.2012.08.018
Reference
PMID:14685853
  Authors
Zafrani ES
  Title
Non-alcoholic fatty liver disease: an emerging pathological spectrum.
  Journal
Virchows Arch 444:3-12 (2004)
DOI:10.1007/s00428-003-0943-7
Reference
PMID:12891546
  Authors
Feldstein AE, Canbay A, Angulo P, Taniai M, Burgart LJ, Lindor KD, Gores GJ
  Title
Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis.
  Journal
Gastroenterology 125:437-43 (2003)
DOI:10.1016/S0016-5085(03)00907-7
Reference
PMID:16406828
  Authors
Begriche K, Igoudjil A, Pessayre D, Fromenty B
  Title
Mitochondrial dysfunction in NASH: causes, consequences and possible means to prevent it.
  Journal
Mitochondrion 6:1-28 (2006)
DOI:10.1016/j.mito.2005.10.004
Reference
PMID:9285483
  Authors
Leonarduzzi G, Scavazza A, Biasi F, Chiarpotto E, Camandola S, Vogel S, Dargel R, Poli G
  Title
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.
  Journal
FASEB J 11:851-7 (1997)
DOI:10.1096/fasebj.11.11.9285483
Reference
PMID:21145844
  Authors
Malhi H, Kaufman RJ
  Title
Endoplasmic reticulum stress in liver disease.
  Journal
J Hepatol 54:795-809 (2011)
DOI:10.1016/j.jhep.2010.11.005
Reference
PMID:18242193
  Authors
Mantena SK, King AL, Andringa KK, Eccleston HB, Bailey SM
  Title
Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases.
  Journal
Free Radic Biol Med 44:1259-72 (2008)
DOI:10.1016/j.freeradbiomed.2007.12.029
Reference
PMID:18061659
  Authors
Serviddio G, Sastre J, Bellanti F, Vina J, Vendemiale G, Altomare E
  Title
Mitochondrial involvement in non-alcoholic steatohepatitis.
  Journal
Mol Aspects Med 29:22-35 (2008)
DOI:10.1016/j.mam.2007.09.014
Reference
PMID:23299992
  Authors
Begriche K, Massart J, Robin MA, Bonnet F, Fromenty B
  Title
Mitochondrial adaptations and dysfunctions in nonalcoholic fatty liver disease.
  Journal
Hepatology 58:1497-507 (2013)
DOI:10.1002/hep.26226
Related
pathway
nvs00061  Fatty acid biosynthesis
nvs00190  Oxidative phosphorylation
nvs03320  PPAR signaling pathway
nvs04141  Protein processing in endoplasmic reticulum
nvs04151  PI3K-Akt signaling pathway
nvs04210  Apoptosis
nvs04668  TNF signaling pathway
nvs04920  Adipocytokine signaling pathway
nvs04930  Type II diabetes mellitus
KO pathway
ko04932   

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