KEGG   PATHWAY: mmu04932
Entry
mmu04932                    Pathway                                
Name
Non-alcoholic fatty liver disease - Mus musculus (house mouse)
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
mmu04932  Non-alcoholic fatty liver disease
mmu04932

Organism
Mus musculus (house mouse) [GN:mmu]
Gene
16193  Il6; interleukin 6 [KO:K05405]
16194  Il6ra; interleukin 6 receptor, alpha [KO:K05055]
12702  Socs3; suppressor of cytokine signaling 3 [KO:K04696]
21926  Tnf; tumor necrosis factor [KO:K03156]
21937  Tnfrsf1a; tumor necrosis factor receptor superfamily, member 1a [KO:K03158]
18033  Nfkb1; nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105 [KO:K02580]
19697  Rela; v-rel reticuloendotheliosis viral oncogene homolog A (avian) [KO:K04735]
16334  Ins2; insulin II [KO:K04526]
16333  Ins1; insulin I [KO:K04526]
16337  Insr; insulin receptor [KO:K04527] [EC:2.7.10.1]
16367  Irs1; insulin receptor substrate 1 [KO:K16172]
384783  Irs2; insulin receptor substrate 2 [KO:K07187]
18706  Pik3ca; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
18707  Pik3cd; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
74769  Pik3cb; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
18709  Pik3r2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
18708  Pik3r1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
18710  Pik3r3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
11651  Akt1; thymoma viral proto-oncogene 1 [KO:K04456] [EC:2.7.11.1]
11652  Akt2; thymoma viral proto-oncogene 2 [KO:K04456] [EC:2.7.11.1]
23797  Akt3; thymoma viral proto-oncogene 3 [KO:K04456] [EC:2.7.11.1]
606496  Gsk3a; glycogen synthase kinase 3 alpha [KO:K08822] [EC:2.7.11.26]
56637  Gsk3b; glycogen synthase kinase 3 beta [KO:K03083] [EC:2.7.11.26]
22259  Nr1h3; nuclear receptor subfamily 1, group H, member 3 [KO:K08536]
20181  Rxra; retinoid X receptor alpha [KO:K08524]
20787  Srebf1; sterol regulatory element binding transcription factor 1 [KO:K07197]
21428  Mlx; MAX-like protein X [KO:K09113]
208104  Mlxip; MLX interacting protein [KO:K09113]
58805  Mlxipl; MLX interacting protein-like [KO:K09113]
18770  Pklr; pyruvate kinase liver and red blood cell [KO:K12406] [EC:2.7.1.40]
16846  Lep; leptin [KO:K05424]
16847  Lepr; leptin receptor [KO:K05062]
11450  Adipoq; adiponectin, C1Q and collagen domain containing [KO:K07296]
72674  Adipor1; adiponectin receptor 1 [KO:K07297]
68465  Adipor2; adiponectin receptor 2 [KO:K07297]
105787  Prkaa1; protein kinase, AMP-activated, alpha 1 catalytic subunit [KO:K07198] [EC:2.7.11.31]
108079  Prkaa2; protein kinase, AMP-activated, alpha 2 catalytic subunit [KO:K07198] [EC:2.7.11.31]
19079  Prkab1; protein kinase, AMP-activated, beta 1 non-catalytic subunit [KO:K07199]
108097  Prkab2; protein kinase, AMP-activated, beta 2 non-catalytic subunit [KO:K07199]
19082  Prkag1; protein kinase, AMP-activated, gamma 1 non-catalytic subunit [KO:K07200]
241113  Prkag3; protein kinase, AMP-activated, gamma 3 non-catalytic subunit [KO:K07200]
108099  Prkag2; protein kinase, AMP-activated, gamma 2 non-catalytic subunit [KO:K07200]
26416  Mapk14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
19094  Mapk11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
29857  Mapk12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
26415  Mapk13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
19013  Ppara; peroxisome proliferator activated receptor alpha [KO:K07294]
19016  Pparg; peroxisome proliferator activated receptor gamma [KO:K08530]
12540  Cdc42; cell division cycle 42 [KO:K04393]
19353  Rac1; Rac family small GTPase 1 [KO:K04392]
26403  Map3k11; mitogen-activated protein kinase kinase kinase 11 [KO:K04419] [EC:2.7.11.25]
26419  Mapk8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
26420  Mapk9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
26414  Mapk10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
16396  Itch; itchy, E3 ubiquitin protein ligase [KO:K05632] [EC:2.3.2.26]
78943  Ern1; endoplasmic reticulum to nucleus signalling 1 [KO:K08852] [EC:2.7.11.1 3.1.26.-]
22030  Traf2; TNF receptor-associated factor 2 [KO:K03173] [EC:2.3.2.27]
26408  Map3k5; mitogen-activated protein kinase kinase kinase 5 [KO:K04426] [EC:2.7.11.25]
14281  Fos; FBJ osteosarcoma oncogene [KO:K04379]
16476  Jun; jun proto-oncogene [KO:K04448]
16175  Il1a; interleukin 1 alpha [KO:K04383]
16176  Il1b; interleukin 1 beta [KO:K04519]
16150  Ikbkb; inhibitor of kappaB kinase beta [KO:K07209] [EC:2.7.11.10]
22433  Xbp1; X-box binding protein 1 [KO:K09027]
12606  Cebpa; CCAAT/enhancer binding protein alpha [KO:K09055]
13106  Cyp2e1; cytochrome P450, family 2, subfamily e, polypeptide 1 [KO:K07415] [EC:1.14.14.-]
14103  Fasl; Fas ligand [KO:K04389]
21803  Tgfb1; transforming growth factor, beta 1 [KO:K13375]
13666  Eif2ak3; eukaryotic translation initiation factor 2 alpha kinase 3 [KO:K08860] [EC:2.7.11.1]
13665  Eif2s1; eukaryotic translation initiation factor 2, subunit 1 alpha [KO:K03237]
11911  Atf4; activating transcription factor 4 [KO:K04374]
13198  Ddit3; DNA-damage inducible transcript 3 [KO:K04452]
12125  Bcl2l11; BCL2 like 11 [KO:K16341]
12028  Bax; BCL2-associated X protein [KO:K02159]
14102  Fas; Fas cell surface death receptor [KO:K04390]
12370  Casp8; caspase 8 [KO:K04398] [EC:3.4.22.61]
12122  Bid; BH3 interacting domain death agonist [KO:K04726]
13063  Cycs; cytochrome c, somatic [KO:K08738]
13067  Cyct; cytochrome c, testis [KO:K08738]
12367  Casp3; caspase 3 [KO:K02187] [EC:3.4.22.56]
12369  Casp7; caspase 7 [KO:K04397] [EC:3.4.22.60]
17995  Ndufv1; NADH:ubiquinone oxidoreductase core subunit V1 [KO:K03942] [EC:7.1.1.2]
72900  Ndufv2; NADH:ubiquinone oxidoreductase core subunit V2 [KO:K03943] [EC:7.1.1.2]
78330  Ndufv3; NADH:ubiquinone oxidoreductase core subunit V3 [KO:K03944]
54405  Ndufa1; NADH:ubiquinone oxidoreductase subunit A1 [KO:K03945]
17991  Ndufa2; NADH:ubiquinone oxidoreductase subunit A2 [KO:K03946]
66091  Ndufa3; NADH:ubiquinone oxidoreductase subunit A3 [KO:K03947]
17992  Ndufa4; Ndufa4, mitochondrial complex associated [KO:K03948]
407790  Ndufa4l2; Ndufa4, mitochondrial complex associated like 2 [KO:K03948]
68202  Ndufa5; NADH:ubiquinone oxidoreductase subunit A5 [KO:K03949]
100502727  Gm19340; predicted gene, 19340 [KO:K03949]
67130  Ndufa6; NADH:ubiquinone oxidoreductase subunit A6 [KO:K03950]
66416  Ndufa7; NADH:ubiquinone oxidoreductase subunit A7 [KO:K03951]
68375  Ndufa8; NADH:ubiquinone oxidoreductase subunit A8 [KO:K03952]
66108  Ndufa9; NADH:ubiquinone oxidoreductase subunit A9 [KO:K03953]
67273  Ndufa10; NADH:ubiquinone oxidoreductase subunit A10 [KO:K03954]
70316  Ndufab1; NADH:ubiquinone oxidoreductase subunit AB1 [KO:K03955]
102634451  Ndufab1-ps; NADH:ubiquinone oxidoreductase subunit AB1b [KO:K03955]
69875  Ndufa11; NADH:ubiquinone oxidoreductase subunit A11 [KO:K03956]
66414  Ndufa12; NADH:ubiquinone oxidoreductase subunit A12 [KO:K11352]
67184  Ndufa13; NADH:ubiquinone oxidoreductase subunit A13 [KO:K11353]
102631912  Ndufb1; NADH:ubiquinone oxidoreductase subunit B1 [KO:K03957]
68198  Ndufb2; NADH:ubiquinone oxidoreductase subunit B2 [KO:K03958]
66495  Ndufb3; NADH:ubiquinone oxidoreductase subunit B3 [KO:K03959]
68194  Ndufb4; NADH:ubiquinone oxidoreductase subunit B4 [KO:K03960]
100042503  Ndufb4b; NADH:ubiquinone oxidoreductase subunit B4B [KO:K03960]
100041273  Ndufb4c; NADH:ubiquinone oxidoreductase subunit B4C [KO:K03960]
66046  Ndufb5; NADH:ubiquinone oxidoreductase subunit B5 [KO:K03961]
230075  Ndufb6; NADH:ubiquinone oxidoreductase subunit B6 [KO:K03962]
66916  Ndufb7; NADH:ubiquinone oxidoreductase subunit B7 [KO:K03963]
67264  Ndufb8; NADH:ubiquinone oxidoreductase subunit B8 [KO:K03964]
66218  Ndufb9; NADH:ubiquinone oxidoreductase subunit B9 [KO:K03965]
68342  Ndufb10; NADH:ubiquinone oxidoreductase subunit B10 [KO:K03966]
104130  Ndufb11; NADH:ubiquinone oxidoreductase subunit B11 [KO:K11351]
227197  Ndufs1; NADH:ubiquinone oxidoreductase core subunit S1 [KO:K03934] [EC:7.1.1.2]
226646  Ndufs2; NADH:ubiquinone oxidoreductase core subunit S2 [KO:K03935] [EC:7.1.1.2]
68349  Ndufs3; NADH:ubiquinone oxidoreductase core subunit S3 [KO:K03936] [EC:7.1.1.2]
17993  Ndufs4; NADH:ubiquinone oxidoreductase core subunit S4 [KO:K03937]
595136  Ndufs5; NADH:ubiquinone oxidoreductase core subunit S5 [KO:K03938]
407785  Ndufs6; NADH:ubiquinone oxidoreductase core subunit S6 [KO:K03939]
623286  Ndufs6b; NADH:ubiquinone oxidoreductase subunit S6B [KO:K03939]
75406  Ndufs7; NADH:ubiquinone oxidoreductase core subunit S7 [KO:K03940] [EC:7.1.1.2]
225887  Ndufs8; NADH:ubiquinone oxidoreductase core subunit S8 [KO:K03941] [EC:7.1.1.2]
66377  Ndufc1; NADH:ubiquinone oxidoreductase subunit C1 [KO:K03967]
68197  Ndufc2; NADH:ubiquinone oxidoreductase subunit C2 [KO:K03968]
66945  Sdha; succinate dehydrogenase complex, subunit A, flavoprotein (Fp) [KO:K00234] [EC:1.3.5.1]
67680  Sdhb; succinate dehydrogenase complex, subunit B, iron sulfur (Ip) [KO:K00235] [EC:1.3.5.1]
66052  Sdhc; succinate dehydrogenase complex, subunit C, integral membrane protein [KO:K00236]
66925  Sdhd; succinate dehydrogenase complex, subunit D, integral membrane protein [KO:K00237]
66694  Uqcrfs1; ubiquinol-cytochrome c reductase, Rieske iron-sulfur polypeptide 1 [KO:K00411] [EC:7.1.1.8]
17711  CYTB; cytochrome b [KO:K00412]
66445  Cyc1; cytochrome c-1 [KO:K00413]
22273  Uqcrc1; ubiquinol-cytochrome c reductase core protein 1 [KO:K00414]
67003  Uqcrc2; ubiquinol cytochrome c reductase core protein 2 [KO:K00415]
66576  Uqcrh; ubiquinol-cytochrome c reductase hinge protein [KO:K00416]
67530  Uqcrb; ubiquinol-cytochrome c reductase binding protein [KO:K00417]
22272  Uqcrq; ubiquinol-cytochrome c reductase, complex III subunit VII [KO:K00418]
66152  Uqcr10; ubiquinol-cytochrome c reductase, complex III subunit X [KO:K00419]
102633050  Gm6293; predicted pseudogene 6293 [KO:K00419]
66594  Uqcr11; ubiquinol-cytochrome c reductase, complex III subunit XI [KO:K00420]
17710  COX3; cytochrome c oxidase subunit III [KO:K02262]
17708  COX1; cytochrome c oxidase subunit I [KO:K02256] [EC:7.1.1.9]
17709  COX2; cytochrome c oxidase subunit II [KO:K02261]
12857  Cox4i1; cytochrome c oxidase subunit 4I1 [KO:K02263]
84682  Cox4i2; cytochrome c oxidase subunit 4I2 [KO:K02263]
12858  Cox5a; cytochrome c oxidase subunit 5A [KO:K02264]
102633230  Gm11633; predicted gene 11633 [KO:K02264]
12859  Cox5b; cytochrome c oxidase subunit 5B [KO:K02265]
12861  Cox6a1; cytochrome c oxidase subunit 6A1 [KO:K02266]
12862  Cox6a2; cytochrome c oxidase subunit 6A2 [KO:K02266]
110323  Cox6b1; cytochrome c oxidase, subunit 6B1 [KO:K02267]
333182  Cox6b2; cytochrome c oxidase subunit 6B2 [KO:K02267]
12864  Cox6c; cytochrome c oxidase subunit 6C [KO:K02268]
12866  Cox7a2; cytochrome c oxidase subunit 7A2 [KO:K02270]
12865  Cox7a1; cytochrome c oxidase subunit 7A1 [KO:K02270]
20463  Cox7a2l; cytochrome c oxidase subunit 7A2 like [KO:K02270]
66142  Cox7b; cytochrome c oxidase subunit 7B [KO:K02271]
78174  Cox7b2; cytochrome c oxidase subunit 7B2 [KO:K02271]
12867  Cox7c; cytochrome c oxidase subunit 7C [KO:K02272]
12868  Cox8a; cytochrome c oxidase subunit 8A [KO:K02273]
12869  Cox8b; cytochrome c oxidase subunit 8B [KO:K02273]
75483  Cox8c; cytochrome c oxidase subunit 8C [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
mmu00061  Fatty acid biosynthesis
mmu00190  Oxidative phosphorylation
mmu03320  PPAR signaling pathway
mmu04141  Protein processing in endoplasmic reticulum
mmu04151  PI3K-Akt signaling pathway
mmu04210  Apoptosis
mmu04668  TNF signaling pathway
mmu04920  Adipocytokine signaling pathway
mmu04930  Type II diabetes mellitus
KO pathway
ko04932   
LinkDB

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