KEGG   PATHWAY: setr04932
Entry
setr04932                   Pathway                                
Name
Non-alcoholic fatty liver disease - Suncus etruscus (white-toothed pygmy shrew)
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
setr04932  Non-alcoholic fatty liver disease
setr04932

Disease
H01333  Non-alcoholic fatty liver disease
Organism
Suncus etruscus (white-toothed pygmy shrew) [GN:setr]
Gene
125994825  [KO:K04393]
125994826  NDUFB8; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 8, mitochondrial [KO:K03964]
125994849  [KO:K02270]
125994946  CASP7; caspase-7 [KO:K04397] [EC:3.4.22.60]
125996221  TNF; tumor necrosis factor [KO:K03156]
125996324  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
125996366  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
125996596  [KO:K03945]
125997212  [KO:K00413]
125997374  NDUFB9; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 9 [KO:K03965]
125997442  [KO:K02270]
125998082  PPARG; peroxisome proliferator-activated receptor gamma [KO:K08530]
125998124  [KO:K11351]
125998229  [KO:K02272]
125998704  [KO:K04393]
125999227  [KO:K07297]
125999297  NDUFB11; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 11, mitochondrial [KO:K11351]
125999312  [KO:K02271]
125999564  NDUFA1; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1 [KO:K03945]
126000044  PRKAA1; LOW QUALITY PROTEIN: 5'-AMP-activated protein kinase catalytic subunit alpha-1 [KO:K07198] [EC:2.7.11.31]
126000573  [KO:K00417]
126000749  [KO:K02266]
126000779  SDHA; succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial isoform X1 [KO:K00234] [EC:1.3.5.1]
126000803  NDUFS6; NADH dehydrogenase [ubiquinone] iron-sulfur protein 6, mitochondrial [KO:K03939]
126000917  NDUFB10; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 10 isoform X1 [KO:K03966]
126000955  NDUFS4; NADH dehydrogenase [ubiquinone] iron-sulfur protein 4, mitochondrial [KO:K03937]
126000959  [KO:K02270]
126000960  [KO:K00235] [EC:1.3.5.1]
126001053  MLXIP; MLX-interacting protein [KO:K09113]
126001122  IRS1; insulin receptor substrate 1 [KO:K16172]
126001552  PIK3R1; LOW QUALITY PROTEIN: phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
126001663  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
126001695  [KO:K02266]
126001808  [KO:K03949]
126002018  NDUFA4; cytochrome c oxidase subunit NDUFA4 [KO:K03948]
126002106  [KO:K08738]
126003496  [KO:K02270]
126003626  NDUFB1; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 1 [KO:K03957]
126003788  NDUFV2; NADH dehydrogenase [ubiquinone] flavoprotein 2, mitochondrial [KO:K03943] [EC:7.1.1.2]
126003827  NDUFC1; NADH dehydrogenase [ubiquinone] 1 subunit C1, mitochondrial [KO:K03967]
126004042  FOS; protein c-Fos [KO:K04379]
126004063  EIF2S1; eukaryotic translation initiation factor 2 subunit 1 [KO:K03237]
126004198  ADIPOR1; adiponectin receptor protein 1 [KO:K07297]
126004362  [KO:K02272]
126004572  [KO:K02270]
126005441  NDUFA5; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 5 [KO:K03949]
126006180  PPARA; peroxisome proliferator-activated receptor alpha [KO:K07294]
126006273  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
126006324  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
126006336  NDUFA6; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 6 [KO:K03950]
126006354  [KO:K02272]
126006370  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
126006407  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
126006582  NDUFA9; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9, mitochondrial [KO:K03953]
126006611  SDHB; succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial [KO:K00235] [EC:1.3.5.1]
126006650  [KO:K00416]
126006652  [KO:K00416]
126006887  [KO:K02187] [EC:3.4.22.56]
126006951  TNFRSF1A; LOW QUALITY PROTEIN: tumor necrosis factor receptor superfamily member 1A [KO:K03158]
126007206  [KO:K02187] [EC:3.4.22.56]
126007207  [KO:K02187] [EC:3.4.22.56]
126007266  [KO:K07297]
126008808  NDUFA8; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 8 [KO:K03952]
126008957  NDUFA10; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10, mitochondrial [KO:K03954]
126008988  NDUFB3; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 3 [KO:K03959]
126008992  [KO:K02267]
126009006  NDUFS1; LOW QUALITY PROTEIN: NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial [KO:K03934] [EC:7.1.1.2]
126009008  CASP8; caspase-8 [KO:K04398] [EC:3.4.22.61]
126009211  [KO:K11352]
126009254  TRAF2; TNF receptor-associated factor 2 [KO:K03173] [EC:2.3.2.27]
126009491  [KO:K00417]
126009498  [KO:K02268]
126009545  RXRA; retinoic acid receptor RXR-alpha [KO:K08524]
126009692  NDUFB6; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 6 [KO:K03962]
126009755  [KO:K08738]
126010787  [KO:K03967]
126010821  [KO:K03948]
126010979  JUN; transcription factor Jun [KO:K04448]
126010983  PRKAA2; LOW QUALITY PROTEIN: 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
126011086  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
126011308  CDC42; cell division control protein 42 homolog isoform X1 [KO:K04393]
126011325  [KO:K00237]
126011360  NDUFS5; NADH dehydrogenase [ubiquinone] iron-sulfur protein 5 [KO:K03938]
126011371  [KO:K00416]
126011378  [KO:K03957]
126011490  [KO:K03945]
126011501  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
126011639  LEPR; leptin receptor [KO:K05062]
126011924  LEP; leptin [KO:K05424]
126011986  ADIPOQ; adiponectin [KO:K07296]
126012035  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
126012036  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
126012058  NDUFB2; LOW QUALITY PROTEIN: NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 2, mitochondrial [KO:K03958]
126012094  NDUFB5; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 5, mitochondrial [KO:K03961]
126013264  NDUFC2; NADH dehydrogenase [ubiquinone] 1 subunit C2 [KO:K03968]
126013417  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
126013516  [KO:K08738]
126013519  [KO:K03967]
126013605  [KO:K02268]
126013653  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
126013658  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
126013793  [KO:K03968]
126013804  [KO:K02270]
126014052  [KO:K00414]
126014166  SDHC; succinate dehydrogenase cytochrome b560 subunit, mitochondrial [KO:K00236]
126014170  NDUFS2; NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, mitochondrial [KO:K03935] [EC:7.1.1.2]
126014825  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
126015454  [KO:K03950]
126015552  IRS2; insulin receptor substrate 2 [KO:K07187]
126015663  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
126015739  [KO:K08738]
126015850  [KO:K03939]
126015993  [KO:K02264]
126016071  [KO:K08738]
126016123  [KO:K02270]
126016153  SDHD; succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial [KO:K00237]
126016565  ERN1; serine/threonine-protein kinase/endoribonuclease IRE1 [KO:K08852] [EC:2.7.11.1 3.1.26.-]
126017286  ITCH; E3 ubiquitin-protein ligase Itchy homolog isoform X1 [KO:K05632] [EC:2.3.2.26]
126017461  [KO:K02263]
126017831  NDUFS3; NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial [KO:K03936] [EC:7.1.1.2]
126017903  [KO:K02270]
126017928  NR1H3; oxysterols receptor LXR-alpha [KO:K08536]
126018017  [KO:K02272]
126018025  MAP3K11; mitogen-activated protein kinase kinase kinase 11 [KO:K04419] [EC:2.7.11.25]
126018299  [KO:K04393]
126018732  MLX; max-like protein X isoform X1 [KO:K09113]
126018795  NDUFV1; NADH dehydrogenase [ubiquinone] flavoprotein 1, mitochondrial [KO:K03942] [EC:7.1.1.2]
126018992  [KO:K00418]
126019025  RELA; transcription factor p65 [KO:K04735]
126019082  NDUFS8; NADH dehydrogenase [ubiquinone] iron-sulfur protein 8, mitochondrial [KO:K03941] [EC:7.1.1.2]
126019098  INS; insulin [KO:K04526]
126020038  [KO:K08738]
126020042  [KO:K08738]
126020094  [KO:K02271]
126020133  IL6R; interleukin-6 receptor subunit alpha [KO:K05055]
126020141  PKLR; pyruvate kinase PKLR [KO:K12406] [EC:2.7.1.40]
126020754  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
126021964  NDUFA12; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 12 [KO:K11352]
126022241  DDIT3; DNA damage-inducible transcript 3 protein [KO:K04452]
126022243  NDUFA4L2; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 4-like 2 [KO:K03948]
126022342  ADIPOR2; adiponectin receptor protein 2 [KO:K07297]
126022354  [KO:K02267]
126022562  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200]
126022683  BID; BH3-interacting domain death agonist [KO:K04726]
126022760  [KO:K02270]
126023893  [KO:K02270]
126023898  [KO:K03965]
126023995  IL1A; interleukin-1 alpha [KO:K04383]
126023999  BCL2L11; bcl-2-like protein 11 [KO:K16341]
126024011  [KO:K08738]
126024019  IL1B; interleukin-1 beta [KO:K04519]
126024081  [KO:K00235] [EC:1.3.5.1]
126024439  [KO:K02265]
126024479  EIF2AK3; eukaryotic translation initiation factor 2-alpha kinase 3 [KO:K08860] [EC:2.7.11.1]
126024665  [KO:K04393]
126025659  NDUFV3; NADH dehydrogenase [ubiquinone] flavoprotein 3, mitochondrial [KO:K03944]
126026123  [KO:K03958]
126026205  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
126026233  NDUFB4; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 4 [KO:K03960]
126027062  NDUFA2; LOW QUALITY PROTEIN: NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 2 [KO:K03946]
126027215  BAX; apoptosis regulator BAX isoform X1 [KO:K02159]
126027263  [KO:K00411] [EC:7.1.1.8]
126027455  [KO:K00237]
126027544  NFKB1; nuclear factor NF-kappa-B p105 subunit [KO:K02580]
126027634  CEBPA; CCAAT/enhancer-binding protein alpha [KO:K09055]
126027685  [KO:K02267]
126027687  [KO:K02270]
126027782  [KO:K02263]
126027799  [KO:K00418]
126027939  [KO:K03938]
126028075  [KO:K02267]
126028076  NDUFA3; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 3 [KO:K03947]
126028132  GSK3A; glycogen synthase kinase-3 alpha [KO:K08822] [EC:2.7.11.26]
126028133  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
126028183  TGFB1; transforming growth factor beta-1 proprotein [KO:K13375]
126028736  [KO:K04393]
126029560  MLXIPL; carbohydrate-responsive element-binding protein [KO:K09113]
126029640  NDUFS7; NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial isoform X1 [KO:K03940] [EC:7.1.1.2]
126029650  [KO:K00420]
126029694  MAP3K5; mitogen-activated protein kinase kinase kinase 5 [KO:K04426] [EC:2.7.11.25]
126029752  NDUFA11; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 11 [KO:K03956]
126030200  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
126030311  NDUFA13; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 13 [KO:K11353]
126030488  RAC1; ras-related C3 botulinum toxin substrate 1 isoform X1 [KO:K04392]
126030545  NDUFB7; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 7 [KO:K03963]
126030640  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
126030676  [KO:K00419]
126030755  XBP1; LOW QUALITY PROTEIN: X-box-binding protein 1 [KO:K09027]
126030966  NDUFAB1; acyl carrier protein, mitochondrial [KO:K03955]
126030981  [KO:K02266]
126031102  [KO:K08738]
126031127  INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
126031189  NDUFA7; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 7 isoform X1 [KO:K03951]
126031235  [KO:K00415]
126032054  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
126032265  CXCL8; interleukin-8 [KO:K10030]
126033346  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
126033458  [KO:K04397] [EC:3.4.22.60]
126033572  [KO:K07415] [EC:1.14.14.-]
126033690  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
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
setr00061  Fatty acid biosynthesis
setr00190  Oxidative phosphorylation
setr03320  PPAR signaling pathway
setr04141  Protein processing in endoplasmic reticulum
setr04151  PI3K-Akt signaling pathway
setr04210  Apoptosis
setr04668  TNF signaling pathway
setr04920  Adipocytokine signaling pathway
setr04930  Type II diabetes mellitus
KO pathway
ko04932   

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