KEGG   PATHWAY: shr04932
Entry
shr04932                    Pathway                                
Name
Non-alcoholic fatty liver disease - Sarcophilus harrisii (Tasmanian devil)
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
shr04932  Non-alcoholic fatty liver disease
shr04932

Organism
Sarcophilus harrisii (Tasmanian devil) [GN:shr]
Gene
105750762  IL6; interleukin-6 [KO:K05405]
100924664  IL6R; interleukin-6 receptor subunit alpha [KO:K05055]
100934360  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
100921875  TNF; tumor necrosis factor [KO:K03156]
100919788  TNFRSF1A; tumor necrosis factor receptor superfamily member 1A [KO:K03158]
100917619  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
100932473  RELA; transcription factor p65 [KO:K04735]
100929204  INSR; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
100918116  IRS1; insulin receptor substrate 1 [KO:K16172]
100924829  IRS2; insulin receptor substrate 2 [KO:K07187]
100931354  IRS4; insulin receptor substrate 4 [KO:K07187]
100929811  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
100932099  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
105749979  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
100926892  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
100924976  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X2 [KO:K02649]
100935230  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
100917987  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100913262  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100925440  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100920192  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
100916753  NR1H3; oxysterols receptor LXR-alpha [KO:K08536]
100926708  RXRA; retinoic acid receptor RXR-alpha isoform X3 [KO:K08524]
100913395  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
100918997  MLX; max-like protein X [KO:K09113]
100913874  MLXIPL; carbohydrate-responsive element-binding protein isoform X1 [KO:K09113]
100928611  MLXIP; MLX-interacting protein [KO:K09113]
100930790  PKLR; pyruvate kinase PKLR isoform X1 [KO:K12406] [EC:2.7.1.40]
100930199  LEP; leptin [KO:K05424]
100914129  LEPR; leptin receptor isoform X2 [KO:K05062]
100924674  ADIPOQ; adiponectin [KO:K07296]
100924677  ADIPOR2; adiponectin receptor protein 2 [KO:K07297]
100920823  ADIPOR1; adiponectin receptor protein 1 isoform X1 [KO:K07297]
100926139  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
100928944  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
100919221  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
105750525  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
100918024  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
100919530  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
100927282  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
100928729  MAPK12; mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
100928990  MAPK11; LOW QUALITY PROTEIN: mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
100925013  MAPK14; mitogen-activated protein kinase 14 isoform X2 [KO:K04441] [EC:2.7.11.24]
100925447  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
100917093  PPARA; peroxisome proliferator-activated receptor alpha [KO:K07294]
100934154  PPARG; peroxisome proliferator-activated receptor gamma isoform X1 [KO:K08530]
100918370  CDC42; cell division control protein 42 homolog isoform X1 [KO:K04393]
100919657  RAC1; ras-related C3 botulinum toxin substrate 1 isoform X1 [KO:K04392]
100932989  MAP3K11; mitogen-activated protein kinase kinase kinase 11 [KO:K04419] [EC:2.7.11.25]
100930815  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
100928480  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
100924267  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
100926872  ITCH; E3 ubiquitin-protein ligase Itchy homolog [KO:K05632] [EC:2.3.2.26]
100935398  ERN1; serine/threonine-protein kinase/endoribonuclease IRE1 [KO:K08852] [EC:2.7.11.1 3.1.26.-]
100934749  TRAF2; TNF receptor-associated factor 2 isoform X1 [KO:K03173] [EC:2.3.2.27]
100917439  MAP3K5; mitogen-activated protein kinase kinase kinase 5 [KO:K04426] [EC:2.7.11.25]
100924435  FOS; proto-oncogene c-Fos [KO:K04379]
116423739  JUN; transcription factor AP-1 [KO:K04448]
105749132  IL1A; interleukin-1 alpha [KO:K04383]
100922350  IL1B; interleukin-1 beta [KO:K04519]
100928932  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
100933113  XBP1; LOW QUALITY PROTEIN: X-box-binding protein 1 [KO:K09027]
100933872  CEBPA; CCAAT/enhancer-binding protein alpha [KO:K09055]
100919776  FASLG; tumor necrosis factor ligand superfamily member 6 isoform X1 [KO:K04389]
100933600  CXCL8; interleukin-8 [KO:K10030]
100932607  TGFB1; LOW QUALITY PROTEIN: transforming growth factor beta-1 proprotein [KO:K13375]
100915385  EIF2AK3; eukaryotic translation initiation factor 2-alpha kinase 3 isoform X1 [KO:K08860] [EC:2.7.11.1]
100921025  EIF2S1; eukaryotic translation initiation factor 2 subunit 1 [KO:K03237]
100913697  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
100931338  DDIT3; DNA damage-inducible transcript 3 protein [KO:K04452]
100932232  BCL2L11; LOW QUALITY PROTEIN: bcl-2-like protein 11 [KO:K16341]
105749219  FAS; tumor necrosis factor receptor superfamily member 6 [KO:K04390]
100931580  CASP8; caspase-8 [KO:K04398] [EC:3.4.22.61]
100929676  BID; BH3-interacting domain death agonist [KO:K04726]
100919671  cytochrome c 2 [KO:K08738]
111721251  cytochrome c [KO:K08738]
100922757  caspase-3-like [KO:K02187] [EC:3.4.22.56]
100922500  CASP3; caspase-3 [KO:K02187] [EC:3.4.22.56]
100927801  CASP7; caspase-7 [KO:K04397] [EC:3.4.22.60]
100934645  NDUFV1; NADH dehydrogenase [ubiquinone] flavoprotein 1, mitochondrial [KO:K03942] [EC:7.1.1.2]
100928428  NDUFV2; LOW QUALITY PROTEIN: NADH dehydrogenase [ubiquinone] flavoprotein 2, mitochondrial [KO:K03943] [EC:7.1.1.2]
100919401  LOW QUALITY PROTEIN: uncharacterized protein LOC100919401 [KO:K03944]
100919666  uncharacterized protein LOC100919666 [KO:K03944]
100933088  NDUFA1; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1 [KO:K03945]
100929783  NDUFA2; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 2 [KO:K03946]
100929856  NDUFA4L2; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 4-like 2 [KO:K03948]
116419640  NDUFA4; cytochrome c oxidase subunit NDUFA4 [KO:K03948]
100924322  NDUFA5; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 5 isoform X1 [KO:K03949]
100919967  NDUFA6; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 6 [KO:K03950]
100918785  NDUFA7; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 7 [KO:K03951]
100913375  NDUFA8; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 8 [KO:K03952]
100933750  NDUFA9; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9, mitochondrial [KO:K03953]
100915617  NDUFA10; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10, mitochondrial [KO:K03954]
100924549  NDUFAB1; acyl carrier protein, mitochondrial [KO:K03955]
100927317  NDUFA11; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 11 [KO:K03956]
100927182  NDUFA12; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 12 [KO:K11352]
100922703  NDUFA13; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 13 [KO:K11353]
100922855  NDUFB1; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 1 [KO:K03957]
100930539  NDUFB2; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 2, mitochondrial [KO:K03958]
100927339  NDUFB3; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 3 [KO:K03959]
100918876  NDUFB4; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 4 [KO:K03960]
100934778  NDUFB5; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 5, mitochondrial [KO:K03961]
111719323  NDUFB6; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 6 [KO:K03962]
100913747  NDUFB7; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 7 [KO:K03963]
100926601  NDUFB8; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 8, mitochondrial [KO:K03964]
116420693  NDUFB9; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 9 [KO:K03965]
100917145  NDUFB10; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 10 [KO:K03966]
100915928  NDUFB11; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 11, mitochondrial [KO:K11351]
100914378  NDUFS1; NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial [KO:K03934] [EC:7.1.1.2]
100922998  NDUFS2; NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, mitochondrial [KO:K03935] [EC:7.1.1.2]
111721451  NDUFS3; NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial [KO:K03936] [EC:7.1.1.2]
100930936  NDUFS4; NADH dehydrogenase [ubiquinone] iron-sulfur protein 4, mitochondrial [KO:K03937]
100932609  NDUFS5; NADH dehydrogenase [ubiquinone] iron-sulfur protein 5 [KO:K03938]
100933792  NDUFS6; NADH dehydrogenase [ubiquinone] iron-sulfur protein 6, mitochondrial [KO:K03939]
100922533  NDUFS7; NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial [KO:K03940] [EC:7.1.1.2]
100918238  NDUFS8; NADH dehydrogenase [ubiquinone] iron-sulfur protein 8, mitochondrial [KO:K03941] [EC:7.1.1.2]
100929004  NDUFC1; NADH dehydrogenase [ubiquinone] 1 subunit C1, mitochondrial [KO:K03967]
100928800  NDUFC2; LOW QUALITY PROTEIN: NADH dehydrogenase [ubiquinone] 1 subunit C2 [KO:K03968]
100931806  SDHA; succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial [KO:K00234] [EC:1.3.5.1]
100924299  SDHB; succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial [KO:K00235] [EC:1.3.5.1]
100918297  SDHC; succinate dehydrogenase cytochrome b560 subunit, mitochondrial [KO:K00236]
100916627  SDHD; succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial [KO:K00237]
100920165  cytochrome b-c1 complex subunit Rieske, mitochondrial [KO:K00411] [EC:7.1.1.8]
13826445  CYTB; cytochrome b [KO:K00412]
100923048  cytochrome c1, heme protein, mitochondrial [KO:K00413]
100919227  cytochrome b-c1 complex subunit 1, mitochondrial [KO:K00414]
100935369  cytochrome b-c1 complex subunit 2, mitochondrial [KO:K00415]
100933846  cytochrome b-c1 complex subunit 6, mitochondrial [KO:K00416]
100928777  cytochrome b-c1 complex subunit 7 [KO:K00417]
100934825  cytochrome b-c1 complex subunit 8 [KO:K00418]
100933375  cytochrome b-c1 complex subunit 9 [KO:K00419]
100931111  cytochrome b-c1 complex subunit 10 [KO:K00420]
13826436  COX3; cytochrome c oxidase subunit III [KO:K02262]
13826440  COX1; cytochrome c oxidase subunit I [KO:K02256] [EC:7.1.1.9]
13826435  COX2; cytochrome c oxidase subunit II [KO:K02261]
100924710  cytochrome c oxidase subunit 4 isoform 1, mitochondrial isoform X1 [KO:K02263]
100922691  cytochrome c oxidase subunit 4 isoform 2, mitochondrial isoform X5 [KO:K02263]
100928744  cytochrome c oxidase subunit 5A, mitochondrial [KO:K02264]
100919989  cytochrome c oxidase subunit 5B, mitochondrial [KO:K02265]
100918528  cytochrome c oxidase subunit 6A2, mitochondrial [KO:K02266]
111719270  cytochrome c oxidase subunit 6A1, mitochondrial [KO:K02266]
100922461  cytochrome c oxidase subunit 6B1 [KO:K02267]
100934493  cytochrome c oxidase subunit 6C [KO:K02268]
100921435  cytochrome c oxidase subunit 7A2, mitochondrial [KO:K02270]
100930775  cytochrome c oxidase subunit 7A1, mitochondrial [KO:K02270]
100928083  cytochrome c oxidase subunit 7A-related protein, mitochondrial [KO:K02270]
100922983  cytochrome c oxidase subunit 7A1, mitochondrial-like [KO:K02270]
100932664  cytochrome c oxidase subunit 7B, mitochondrial isoform X1 [KO:K02271]
100933884  cytochrome c oxidase subunit 7C, mitochondrial [KO:K02272]
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
shr00061  Fatty acid biosynthesis
shr00190  Oxidative phosphorylation
shr03320  PPAR signaling pathway
shr04141  Protein processing in endoplasmic reticulum
shr04151  PI3K-Akt signaling pathway
shr04210  Apoptosis
shr04668  TNF signaling pathway
shr04920  Adipocytokine signaling pathway
shr04930  Type II diabetes mellitus
KO pathway
ko04932   
LinkDB

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