KEGG   PATHWAY: hmh04932
Entry
hmh04932                    Pathway                                
Name
Non-alcoholic fatty liver disease - Hylobates moloch (silvery gibbon)
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
hmh04932  Non-alcoholic fatty liver disease
hmh04932

Disease
H01333  Non-alcoholic fatty liver disease
Organism
Hylobates moloch (silvery gibbon) [GN:hmh]
Gene
116456218  FOS; protein c-Fos [KO:K04379]
116456270  [KO:K03959]
116456560  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
116456710  [KO:K02271]
116456788  NDUFS6; NADH dehydrogenase [ubiquinone] iron-sulfur protein 6, mitochondrial [KO:K03939]
116456796  SDHA; succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial [KO:K00234] [EC:1.3.5.1]
116456926  [KO:K02265]
116457035  [KO:K02272]
116457103  [KO:K00417]
116457283  LEPR; leptin receptor [KO:K05062]
116457363  JUN; transcription factor Jun [KO:K04448]
116457630  [KO:K02272]
116457665  [KO:K03947]
116457822  FAS; tumor necrosis factor receptor superfamily member 6 isoform X2 [KO:K04390]
116457860  ADIPOR1; adiponectin receptor protein 1 isoform X1 [KO:K07297]
116457903  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
116458112  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X1 [KO:K07198] [EC:2.7.11.31]
116458229  NDUFB6; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 6 isoform X1 [KO:K03962]
116458344  PPARA; peroxisome proliferator-activated receptor alpha [KO:K07294]
116458518  MAPK12; mitogen-activated protein kinase 12 isoform X2 [KO:K04441] [EC:2.7.11.24]
116458519  MAPK11; mitogen-activated protein kinase 11 isoform X1 [KO:K04441] [EC:2.7.11.24]
116458524  [KO:K02271]
116458613  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
116458727  ERN1; serine/threonine-protein kinase/endoribonuclease IRE1 isoform X1 [KO:K08852] [EC:2.7.11.1 3.1.26.-]
116458807  NDUFA6; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 6 [KO:K03950]
116459021  [KO:K00419]
116459108  [KO:K03949]
116459428  XBP1; LOW QUALITY PROTEIN: X-box-binding protein 1 [KO:K09027]
116459453  BID; BH3-interacting domain death agonist [KO:K04726]
116459642  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
116459649  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
116460115  TNF; tumor necrosis factor isoform X2 [KO:K03156]
116460740  [KO:K02271]
116460769  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
116460777  ITCH; E3 ubiquitin-protein ligase Itchy homolog [KO:K05632] [EC:2.3.2.26]
116461312  [KO:K02263]
116461632  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
116461671  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200]
116462105  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
116462285  NDUFS4; NADH dehydrogenase [ubiquinone] iron-sulfur protein 4, mitochondrial isoform X1 [KO:K03937]
116462643  NDUFB10; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 10 isoform X1 [KO:K03966]
116462749  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
116463128  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
116464026  [KO:K03956]
116464030  [KO:K03956]
116464049  [KO:K00235] [EC:1.3.5.1]
116464170  NDUFC1; NADH dehydrogenase [ubiquinone] 1 subunit C1, mitochondrial [KO:K03967]
116464274  [KO:K03939]
116464279  [KO:K03939]
116466067  CASP3; caspase-3 isoform X1 [KO:K02187] [EC:3.4.22.56]
116466323  [KO:K02265]
116466356  [KO:K03949]
116466514  [KO:K02272]
116466751  PPARG; peroxisome proliferator-activated receptor gamma isoform X1 [KO:K08530]
116466891  NDUFB4; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 4 [KO:K03960]
116466895  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
116467002  CXCL8; interleukin-8 [KO:K10030]
116467557  IRS2; insulin receptor substrate 2 [KO:K07187]
116467991  [KO:K02264]
116468021  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
116468192  [KO:K03948]
116468740  NDUFV2; NADH dehydrogenase [ubiquinone] flavoprotein 2, mitochondrial isoform X2 [KO:K03943] [EC:7.1.1.2]
116468858  [KO:K02270]
116468931  [KO:K02273]
116469010  MAP3K11; mitogen-activated protein kinase kinase kinase 11 [KO:K04419] [EC:2.7.11.25]
116469011  RELA; transcription factor p65 isoform X1 [KO:K04735]
116469089  NDUFV1; NADH dehydrogenase [ubiquinone] flavoprotein 1, mitochondrial isoform X1 [KO:K03942] [EC:7.1.1.2]
116469098  NDUFS8; NADH dehydrogenase [ubiquinone] iron-sulfur protein 8, mitochondrial [KO:K03941] [EC:7.1.1.2]
116469318  PKLR; pyruvate kinase PKLR [KO:K12406] [EC:2.7.1.40]
116469359  IL6R; interleukin-6 receptor subunit alpha isoform X1 [KO:K05055]
116469688  [KO:K03948]
116469796  [KO:K03948]
116470741  [KO:K02263]
116470828  [KO:K00418]
116471025  [KO:K02272]
116471120  [KO:K00415]
116471141  NDUFAB1; acyl carrier protein, mitochondrial [KO:K03955]
116471160  [KO:K08738]
116471190  [KO:K03947]
116471196  [KO:K02266]
116471218  [KO:K03949]
116471600  NDUFA2; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 2 isoform X1 [KO:K03946]
116471795  [KO:K00417]
116471970  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
116472296  FASLG; tumor necrosis factor ligand superfamily member 6 isoform X1 [KO:K04389]
116472520  ADIPOR2; adiponectin receptor protein 2 isoform X2 [KO:K07297]
116472560  NDUFA9; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9, mitochondrial isoform X1 [KO:K03953]
116472781  MAP3K5; mitogen-activated protein kinase kinase kinase 5 isoform X1 [KO:K04426] [EC:2.7.11.25]
116472984  NDUFS5; NADH dehydrogenase [ubiquinone] iron-sulfur protein 5 [KO:K03938]
116473104  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X2 [KO:K02649]
116473111  [KO:K00416]
116473332  SDHC; succinate dehydrogenase cytochrome b560 subunit, mitochondrial isoform X1 [KO:K00236]
116473340  NDUFS2; NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, mitochondrial isoform X1 [KO:K03935] [EC:7.1.1.2]
116473447  [KO:K00414]
116474589  [KO:K03938]
116474873  MLX; max-like protein X isoform X1 [KO:K09113]
116475617  NDUFA8; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 8 [KO:K03952]
116475658  [KO:K03959]
116475838  RXRA; retinoic acid receptor RXR-alpha isoform X1 [KO:K08524]
116475877  TRAF2; TNF receptor-associated factor 2 isoform X3 [KO:K03173] [EC:2.3.2.27]
116476180  [KO:K11351]
116476238  [KO:K03957]
116476267  NDUFS3; NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial [KO:K03936] [EC:7.1.1.2]
116476281  NR1H3; oxysterols receptor LXR-alpha isoform X1 [KO:K08536]
116476737  NDUFC2; NADH dehydrogenase [ubiquinone] 1 subunit C2 [KO:K03968]
116476907  [KO:K08738]
116476941  SDHD; succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial isoform X1 [KO:K00237]
116477773  MLXIP; MLX-interacting protein isoform X2 [KO:K09113]
116477827  [KO:K02266]
116477841  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
116478225  BAX; apoptosis regulator BAX isoform X3 [KO:K02159]
116478399  NDUFA7; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 7 [KO:K03951]
116478601  NDUFB7; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 7 [KO:K03963]
116478691  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
116478746  NDUFA13; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 13 isoform X1 [KO:K11353]
116478821  [KO:K00411] [EC:7.1.1.8]
116478857  CEBPA; CCAAT/enhancer-binding protein alpha [KO:K09055]
116478869  [KO:K00420]
116478914  [KO:K02267]
116478944  [KO:K02270]
116479108  NDUFA12; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 12 isoform X1 [KO:K11352]
116479184  NDUFA3; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 3 [KO:K03947]
116479218  [KO:K02267]
116479486  INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
116479923  [KO:K03938]
116480043  [KO:K00418]
116480287  [KO:K04392]
116480617  GSK3A; glycogen synthase kinase-3 alpha [KO:K08822] [EC:2.7.11.26]
116480647  TGFB1; transforming growth factor beta-1 proprotein [KO:K13375]
116480683  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
116480828  [KO:K00416]
116480869  DDIT3; DNA damage-inducible transcript 3 protein [KO:K04452]
116481263  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
116481268  NDUFB5; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 5, mitochondrial isoform X1 [KO:K03961]
116481584  [KO:K07415] [EC:1.14.14.-]
116481681  NDUFV3; NADH dehydrogenase [ubiquinone] flavoprotein 3, mitochondrial isoform X1 [KO:K03944]
116481919  [KO:K02264]
116482952  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
116482986  [KO:K02265]
116483082  [KO:K03960]
116483180  EIF2AK3; eukaryotic translation initiation factor 2-alpha kinase 3 [KO:K08860] [EC:2.7.11.1]
116483240  IL1A; interleukin-1 alpha [KO:K04383]
116483283  IL1B; interleukin-1 beta [KO:K04519]
116483343  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
116483374  BCL2L11; bcl-2-like protein 11 isoform X2 [KO:K16341]
116483411  SREBF1; sterol regulatory element-binding protein 1 isoform X2 [KO:K07197]
116483412  CASP7; caspase-7 isoform X1 [KO:K04397] [EC:3.4.22.60]
116483639  [KO:K02270]
116484013  [KO:K00420]
116484067  [KO:K02272]
116484171  NDUFS7; NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial isoform X2 [KO:K03940] [EC:7.1.1.2]
116484546  [KO:K00420]
116484857  NDUFB1; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 1 isoform X1 [KO:K03957]
116485009  NDUFB8; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 8, mitochondrial [KO:K03964]
116485090  [KO:K02273]
116485139  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
116485158  EIF2S1; eukaryotic translation initiation factor 2 subunit 1 [KO:K03237]
116809673  LEP; leptin [KO:K05424]
116809676  [KO:K08738]
116810145  IRS1; insulin receptor substrate 1 [KO:K16172]
116810283  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
116810327  [KO:K04374]
116810400  NDUFS1; NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial [KO:K03934] [EC:7.1.1.2]
116810454  CASP8; caspase-8 isoform X1 [KO:K04398] [EC:3.4.22.61]
116810870  RAC1; ras-related C3 botulinum toxin substrate 1 [KO:K04392]
116811106  [KO:K02271]
116811178  [KO:K03948]
116811446  [KO:K08738]
116811503  [KO:K03960]
116811635  NDUFB11; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 11, mitochondrial [KO:K11351]
116811683  MLXIPL; carbohydrate-responsive element-binding protein isoform X1 [KO:K09113]
116811705  [KO:K00419]
116811998  NDUFA1; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1 [KO:K03945]
116812249  [KO:K03946]
116812505  [KO:K02271]
116812582  [KO:K02271]
116812889  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
116812984  SDHB; succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial [KO:K00235] [EC:1.3.5.1]
116812987  [KO:K08738]
116813051  CDC42; cell division control protein 42 homolog isoform X2 [KO:K04393]
116813186  IL6; interleukin-6 isoform X1 [KO:K05405]
116813443  [KO:K00417]
116813467  [KO:K02268]
116813580  NDUFB9; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 9 isoform X1 [KO:K03965]
116813617  NDUFA4; cytochrome c oxidase subunit NDUFA4 [KO:K03948]
116813689  [KO:K00413]
116814302  NDUFA5; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 5 isoform X1 [KO:K03949]
116814392  [KO:K00237]
116814430  NDUFB2; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 2, mitochondrial isoform X1 [KO:K03958]
116814514  NDUFA10; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10, mitochondrial isoform X3 [KO:K03954]
116814555  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
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
hmh00061  Fatty acid biosynthesis
hmh00190  Oxidative phosphorylation
hmh03320  PPAR signaling pathway
hmh04141  Protein processing in endoplasmic reticulum
hmh04151  PI3K-Akt signaling pathway
hmh04210  Apoptosis
hmh04668  TNF signaling pathway
hmh04920  Adipocytokine signaling pathway
hmh04930  Type II diabetes mellitus
KO pathway
ko04932   

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