KEGG   PATHWAY: bacu04932
Entry
bacu04932                   Pathway                                
Name
Non-alcoholic fatty liver disease - Balaenoptera acutorostrata scammoni (minke whale)
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
bacu04932  Non-alcoholic fatty liver disease
bacu04932

Organism
Balaenoptera acutorostrata scammoni (minke whale) [GN:bacu]
Gene
103008558  IL6; interleukin 6 [KO:K05405]
103019388  IL6R; interleukin 6 receptor [KO:K05055]
103013097  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
103005897  TNF; tumor necrosis factor [KO:K03156]
103016474  TNFRSF1A; TNF receptor superfamily member 1A [KO:K03158]
102999230  NFKB1; nuclear factor kappa B subunit 1 [KO:K02580]
103019614  RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735]
103021022  INS; insulin [KO:K04526]
103018249  INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
103011761  IRS1; insulin receptor substrate 1 [KO:K16172]
103005810  IRS2; insulin receptor substrate 2 [KO:K07187]
103012691  PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
103012931  PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
103014043  PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
103008077  PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
103009307  PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
103007464  PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
103002026  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]
103013147  AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1]
103004139  AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1]
103016833  GSK3A; glycogen synthase kinase 3 alpha [KO:K08822] [EC:2.7.11.26]
102998893  GSK3B; glycogen synthase kinase 3 beta [KO:K03083] [EC:2.7.11.26]
103020980  NR1H3; nuclear receptor subfamily 1 group H member 3 [KO:K08536]
103005517  RXRA; retinoid X receptor alpha [KO:K08524]
103011610  SREBF1; sterol regulatory element binding transcription factor 1 [KO:K07197]
103003427  MLXIPL; MLX interacting protein like [KO:K09113]
103011193  MLXIP; MLX interacting protein [KO:K09113]
103017924  max-like protein X-like [KO:K09113]
103018842  MLX; MLX, MAX dimerization protein [KO:K09113]
103019356  PKLR; pyruvate kinase, liver and RBC [KO:K12406] [EC:2.7.1.40]
103005162  LEP; leptin [KO:K05424]
103001028  LEPR; leptin receptor [KO:K05062]
103012864  ADIPOQ; adiponectin, C1Q and collagen domain containing [KO:K07296]
103008552  ADIPOR1; adiponectin receptor 1 [KO:K07297]
103016602  ADIPOR2; adiponectin receptor 2 [KO:K07297]
103018222  PRKAA2; protein kinase AMP-activated catalytic subunit alpha 2 [KO:K07198] [EC:2.7.11.31]
103019090  PRKAA1; protein kinase AMP-activated catalytic subunit alpha 1 [KO:K07198] [EC:2.7.11.31]
103019135  PRKAB2; protein kinase AMP-activated non-catalytic subunit beta 2 [KO:K07199]
103015065  PRKAB1; protein kinase AMP-activated non-catalytic subunit beta 1 [KO:K07199]
103000853  PRKAG2; protein kinase AMP-activated non-catalytic subunit gamma 2 [KO:K07200]
102999310  PRKAG3; protein kinase AMP-activated non-catalytic subunit gamma 3 [KO:K07200]
103017735  PRKAG1; protein kinase AMP-activated non-catalytic subunit gamma 1 [KO:K07200]
103009947  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
102999798  mitogen-activated protein kinase 12-like [KO:K04441] [EC:2.7.11.24]
103002378  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
103008537  MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
102999493  PPARA; peroxisome proliferator activated receptor alpha [KO:K07294]
103013413  PPARG; peroxisome proliferator activated receptor gamma [KO:K08530]
103008817  CDC42; cell division cycle 42 [KO:K04393]
103007995  RAC1; ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) [KO:K04392]
103004845  MAP3K11; mitogen-activated protein kinase kinase kinase 11 [KO:K04419] [EC:2.7.11.25]
102997603  MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
103007019  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
103008728  MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
103003555  ITCH; itchy E3 ubiquitin protein ligase [KO:K05632] [EC:2.3.2.26]
103016780  ERN1; endoplasmic reticulum to nucleus signaling 1 [KO:K08852] [EC:2.7.11.1 3.1.26.-]
103013880  TRAF2; TNF receptor associated factor 2 [KO:K03173] [EC:2.3.2.27]
102999328  MAP3K5; mitogen-activated protein kinase kinase kinase 5 [KO:K04426] [EC:2.7.11.25]
102997242  FOS; Fos proto-oncogene, AP-1 transcription factor subunit [KO:K04379]
103001311  transcription factor AP-1-like [KO:K04448]
103014668  transcription factor AP-1-like [KO:K04448]
103008155  IL1A; interleukin 1 alpha [KO:K04383]
103008438  IL1B; interleukin 1 beta [KO:K04519]
103015119  IKBKB; inhibitor of nuclear factor kappa B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
103013093  CEBPA; CCAAT/enhancer binding protein alpha [KO:K09055]
102997947  cytochrome P450 2E1-like [KO:K07415] [EC:1.14.14.-]
102999836  FASLG; Fas ligand [KO:K04389]
103006782  CXCL8; C-X-C motif chemokine ligand 8 [KO:K10030]
103002687  TGFB1; transforming growth factor beta 1 [KO:K13375]
103020488  EIF2AK3; eukaryotic translation initiation factor 2 alpha kinase 3 [KO:K08860] [EC:2.7.11.1]
103004526  EIF2S1; eukaryotic translation initiation factor 2 subunit alpha [KO:K03237]
103017770  ATF4; activating transcription factor 4 [KO:K04374]
103018481  DDIT3; DNA damage inducible transcript 3 [KO:K04452]
103003003  BCL2L11; BCL2 like 11 [KO:K16341]
103019528  BAX; BCL2 associated X, apoptosis regulator [KO:K02159]
103020508  FAS; Fas cell surface death receptor [KO:K04390]
103004642  CASP8; caspase 8 [KO:K04398] [EC:3.4.22.61]
103013636  BID; BH3 interacting domain death agonist [KO:K04726]
103017780  cytochrome c 2-like [KO:K08738]
102999215  cytochrome c-like [KO:K08738]
103004375  cytochrome c-like [KO:K08738]
103003361  cytochrome c-like [KO:K08738]
103019939  CASP3; caspase 3 [KO:K02187] [EC:3.4.22.56]
103013605  CASP7; caspase 7 [KO:K04397] [EC:3.4.22.60]
103003730  NDUFV1; NADH:ubiquinone oxidoreductase core subunit V1 [KO:K03942] [EC:7.1.1.2]
103018290  NDUFV2; NADH:ubiquinone oxidoreductase core subunit V2 [KO:K03943] [EC:7.1.1.2]
103020190  NDUFV3; NADH:ubiquinone oxidoreductase subunit V3 [KO:K03944]
103002082  NDUFA2; NADH:ubiquinone oxidoreductase subunit A2 [KO:K03946]
103016522  NDUFA3; NADH:ubiquinone oxidoreductase subunit A3 [KO:K03947]
103008316  NDUFA4; NDUFA4, mitochondrial complex associated [KO:K03948]
103012877  NDUFA4L2; NDUFA4, mitochondrial complex associated like 2 [KO:K03948]
103012110  NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 5-like [KO:K03949]
103006826  NDUFA6; NADH:ubiquinone oxidoreductase subunit A6 [KO:K03950]
103009458  NDUFA7; NADH:ubiquinone oxidoreductase subunit A7 [KO:K03951]
103005817  NDUFA8; NADH:ubiquinone oxidoreductase subunit A8 [KO:K03952]
102999953  NDUFA9; NADH:ubiquinone oxidoreductase subunit A9 [KO:K03953]
103007690  NDUFA10; NADH:ubiquinone oxidoreductase subunit A10 [KO:K03954]
103001609  acyl carrier protein, mitochondrial-like [KO:K03955]
103003298  NDUFAB1; NADH:ubiquinone oxidoreductase subunit AB1 [KO:K03955]
103005308  NDUFA11; NADH:ubiquinone oxidoreductase subunit A11 [KO:K03956]
103014946  NDUFA12; NADH:ubiquinone oxidoreductase subunit A12 [KO:K11352]
103017626  NDUFA13; NADH:ubiquinone oxidoreductase subunit A13 [KO:K11353]
103016811  uncharacterized LOC103016811 [KO:K03957]
103009696  NDUFB2; NADH:ubiquinone oxidoreductase subunit B2 [KO:K03958]
103017454  NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 2, mitochondrial-like [KO:K03958]
103001064  NDUFB3; NADH:ubiquinone oxidoreductase subunit B3 [KO:K03959]
103021069  NDUFB4; NADH:ubiquinone oxidoreductase subunit B4 [KO:K03960]
103000630  NDUFB5; NADH:ubiquinone oxidoreductase subunit B5 [KO:K03961]
103021055  NDUFB6; NADH:ubiquinone oxidoreductase subunit B6 [KO:K03962]
103020517  NDUFB7; NADH:ubiquinone oxidoreductase subunit B7 [KO:K03963]
103011102  NDUFB8; NADH:ubiquinone oxidoreductase subunit B8 [KO:K03964]
103012923  NDUFB9; NADH:ubiquinone oxidoreductase subunit B9 [KO:K03965]
103000659  NDUFB10; NADH:ubiquinone oxidoreductase subunit B10 [KO:K03966]
103001938  NDUFB11; NADH:ubiquinone oxidoreductase subunit B11 [KO:K11351]
103020178  NDUFS1; NADH:ubiquinone oxidoreductase core subunit S1 [KO:K03934] [EC:7.1.1.2]
103013023  NDUFS2; NADH:ubiquinone oxidoreductase core subunit S2 [KO:K03935] [EC:7.1.1.2]
103002843  NDUFS3; NADH:ubiquinone oxidoreductase core subunit S3 [KO:K03936] [EC:7.1.1.2]
103018097  NDUFS4; NADH:ubiquinone oxidoreductase subunit S4 [KO:K03937]
103014501  NDUFS5; NADH:ubiquinone oxidoreductase subunit S5 [KO:K03938]
103001627  NDUFS6; NADH:ubiquinone oxidoreductase subunit S6 [KO:K03939]
102999358  NDUFS7; NADH:ubiquinone oxidoreductase core subunit S7 [KO:K03940] [EC:7.1.1.2]
103006544  NDUFS8; NADH:ubiquinone oxidoreductase core subunit S8 [KO:K03941] [EC:7.1.1.2]
102999688  NDUFC1; NADH:ubiquinone oxidoreductase subunit C1 [KO:K03967]
103013847  NDUFC2; NADH:ubiquinone oxidoreductase subunit C2 [KO:K03968]
103005047  SDHA; succinate dehydrogenase complex flavoprotein subunit A [KO:K00234] [EC:1.3.5.1]
103013798  SDHB; succinate dehydrogenase complex iron sulfur subunit B [KO:K00235] [EC:1.3.5.1]
103010344  SDHC; succinate dehydrogenase complex subunit C [KO:K00236]
103014249  SDHD; succinate dehydrogenase complex subunit D [KO:K00237]
103010509  cytochrome b-c1 complex subunit Rieske, mitochondrial-like [KO:K00411] [EC:7.1.1.8]
103003514  cytochrome c1, heme protein, mitochondrial-like [KO:K00413]
103010896  cytochrome b-c1 complex subunit 1, mitochondrial-like [KO:K00414]
102998746  cytochrome b-c1 complex subunit 2, mitochondrial-like [KO:K00415]
103006696  cytochrome b-c1 complex subunit 6, mitochondrial-like [KO:K00416]
102999929  cytochrome b-c1 complex subunit 7-like [KO:K00417]
103012637  cytochrome b-c1 complex subunit 8-like [KO:K00418]
103013784  cytochrome b-c1 complex subunit 8-like [KO:K00418]
103008919  cytochrome b-c1 complex subunit 9-like [KO:K00419]
103006928  cytochrome b-c1 complex subunit 9-like [KO:K00419]
103010463  cytochrome b-c1 complex subunit 10-like [KO:K00420]
103019629  cytochrome c oxidase subunit 4 isoform 2, mitochondrial-like [KO:K02263]
103015443  cytochrome c oxidase subunit 4 isoform 1, mitochondrial-like [KO:K02263]
103003865  cytochrome c oxidase subunit 5A, mitochondrial-like [KO:K02264]
103015197  cytochrome c oxidase subunit 5B, mitochondrial-like [KO:K02265]
103001279  cytochrome c oxidase subunit 5B, mitochondrial-like [KO:K02265]
103006136  cytochrome c oxidase subunit 6A2, mitochondrial-like [KO:K02266]
103008559  cytochrome c oxidase subunit 6A1, mitochondrial-like [KO:K02266]
103015043  cytochrome c oxidase subunit 6B1-like [KO:K02267]
103005093  cytochrome c oxidase subunit 6B2-like [KO:K02267]
103003421  cytochrome c oxidase subunit 7A1, mitochondrial-like [KO:K02270]
103017759  cytochrome c oxidase subunit 7A-related protein, mitochondrial-like [KO:K02270]
103019426  cytochrome c oxidase subunit 7A2, mitochondrial-like [KO:K02270]
103011737  cytochrome c oxidase subunit 7B2, mitochondrial-like [KO:K02271]
103017687  cytochrome c oxidase subunit 7B, mitochondrial-like [KO:K02271]
103019246  cytochrome c oxidase subunit 7B, mitochondrial-like [KO:K02271]
103013789  cytochrome c oxidase subunit 7C, mitochondrial-like [KO:K02272]
103001251  cytochrome c oxidase subunit 8C, mitochondrial-like [KO:K02273]
103010848  cytochrome c oxidase subunit 8A, mitochondrial-like [KO:K02273]
103010006  cytochrome c oxidase subunit 8C, mitochondrial-like [KO:K02273]
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
bacu00061  Fatty acid biosynthesis
bacu00190  Oxidative phosphorylation
bacu03320  PPAR signaling pathway
bacu04141  Protein processing in endoplasmic reticulum
bacu04151  PI3K-Akt signaling pathway
bacu04210  Apoptosis
bacu04668  TNF signaling pathway
bacu04920  Adipocytokine signaling pathway
bacu04930  Type II diabetes mellitus
KO pathway
ko04932   
LinkDB

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