KEGG   PATHWAY: rno04932
rno04932                    Pathway                                

Non-alcoholic fatty liver disease - Rattus norvegicus (rat)
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.
Human Diseases; Endocrine and metabolic disease
Pathway map
rno04932  Non-alcoholic fatty liver disease

Rattus norvegicus (rat) [GN:rno]
24498  Il6; interleukin-6 precursor [KO:K05405]
24499  Il6r; interleukin-6 receptor subunit alpha precursor [KO:K05055]
89829  Socs3; suppressor of cytokine signaling 3 [KO:K04696]
24835  Tnf; tumor necrosis factor [KO:K03156]
25625  Tnfrsf1a; tumor necrosis factor receptor superfamily member 1A precursor [KO:K03158]
81736  Nfkb1; nuclear factor NF-kappa-B p105 subunit [KO:K02580]
309165  Rela; transcription factor p65 [KO:K04735]
24506  Ins2; insulin-2 preproprotein [KO:K04526]
24505  Ins1; insulin-1 preproprotein [KO:K04526]
24954  Insr; insulin receptor preproprotein [KO:K04527] [EC:]
25467  Irs1; insulin receptor substrate 1 [KO:K16172]
29376  Irs2; insulin receptor substrate 2 [KO:K07187]
85243  Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:]
170911  Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:]
366508  Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:]
25513  Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
60664  Pik3r3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
29741  Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
24185  Akt1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:]
25233  Akt2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:]
29414  Akt3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:]
50686  Gsk3a; glycogen synthase kinase-3 alpha [KO:K08822] [EC:]
84027  Gsk3b; glycogen synthase kinase-3 beta [KO:K03083] [EC:]
58852  Nr1h3; oxysterols receptor LXR-alpha [KO:K08536]
25271  Rxra; retinoic acid receptor RXR-alpha [KO:K08524]
78968  Srebf1; sterol regulatory element-binding protein 1 isoform 1 precursor [KO:K07197]
360631  Mlx; max-like protein X [KO:K09113]
304479  Mlxip; MLX-interacting protein isoform X1 [KO:K09113]
171078  Mlxipl; carbohydrate-responsive element-binding protein [KO:K09113]
24651  Pklr; pyruvate kinase PKLR [KO:K12406] [EC:]
25608  Lep; leptin precursor [KO:K05424]
24536  Lepr; leptin receptor precursor [KO:K05062]
246253  Adipoq; adiponectin precursor [KO:K07296]
312670  Adipor2; adiponectin receptor protein 2 [KO:K07297]
289036  Adipor1; adiponectin receptor protein 1 [KO:K07297]
65248  Prkaa1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 [KO:K07198] [EC:]
78975  Prkaa2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:]
83803  Prkab1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
64562  Prkab2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
25520  Prkag1; 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200]
373545  Prkag2; 5'-AMP-activated protein kinase subunit gamma-2 [KO:K07200]
301518  Prkag3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
81649  Mapk14; mitogen-activated protein kinase 14 [KO:K04441] [EC:]
60352  Mapk12; mitogen-activated protein kinase 12 [KO:K04441] [EC:]
29513  Mapk13; mitogen-activated protein kinase 13 [KO:K04441] [EC:]
689314  Mapk11; mitogen-activated protein kinase 11 [KO:K04441] [EC:]
25747  Ppara; peroxisome proliferator-activated receptor alpha [KO:K07294]
25664  Pparg; peroxisome proliferator-activated receptor gamma isoform 1 [KO:K08530]
64465  Cdc42; cell division control protein 42 homolog [KO:K04393]
363875  Rac1; ras-related C3 botulinum toxin substrate 1 [KO:K04392]
309168  Map3k11; mitogen-activated protein kinase kinase kinase 11 [KO:K04419] [EC:]
25272  Mapk10; mitogen-activated protein kinase 10 isoform 2 [KO:K04440] [EC:]
50658  Mapk9; mitogen-activated protein kinase 9 isoform 2 [KO:K04440] [EC:]
116554  Mapk8; mitogen-activated protein kinase 8 [KO:K04440] [EC:]
311567  Itch; E3 ubiquitin-protein ligase Itchy homolog [KO:K05632] [EC:]
498013  Ern1; serine/threonine-protein kinase/endoribonuclease IRE1 [KO:K08852] [EC: 3.1.26.-]
311786  Traf2; TNF receptor-associated factor 2 [KO:K03173] [EC:]
365057  Map3k5; mitogen-activated protein kinase kinase kinase 5 [KO:K04426] [EC:]
314322  Fos; proto-oncogene c-Fos [KO:K04379]
24516  Jun; transcription factor AP-1 [KO:K04448]
24493  Il1a; interleukin-1 alpha [KO:K04383]
24494  Il1b; interleukin-1 beta [KO:K04519]
84351  Ikbkb; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:]
289754  Xbp1; X-box-binding protein 1 isoform XBP1(U) [KO:K09027]
24252  Cebpa; CCAAT/enhancer-binding protein alpha isoform a [KO:K09055]
25086  Cyp2e1; cytochrome P450 2E1 [KO:K07415] [EC:1.14.14.-]
25385  Faslg; tumor necrosis factor ligand superfamily member 6 [KO:K04389]
59086  Tgfb1; transforming growth factor beta-1 proprotein precursor [KO:K13375]
29702  Eif2ak3; eukaryotic translation initiation factor 2-alpha kinase 3 precursor [KO:K08860] [EC:]
54318  Eif2s1; eukaryotic translation initiation factor 2 subunit 1 [KO:K03237]
79255  Atf4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
29467  Ddit3; DNA damage-inducible transcript 3 protein [KO:K04452]
64547  Bcl2l11; bcl-2-like protein 11 [KO:K16341]
24887  Bax; apoptosis regulator BAX [KO:K02159]
246097  Fas; tumor necrosis factor receptor superfamily member 6 precursor [KO:K04390]
64044  Casp8; caspase-8 [KO:K04398] [EC:]
64625  Bid; BH3-interacting domain death agonist [KO:K04726]
25309  Cycs; cytochrome c, somatic [KO:K08738]
25310  Cyct; cytochrome c, testis-specific [KO:K08738]
100363502  cytochrome c, somatic [KO:K08738]
25402  Casp3; caspase-3 [KO:K02187] [EC:]
64026  Casp7; caspase-7 [KO:K04397] [EC:]
293655  Ndufv1; NADH dehydrogenase [ubiquinone] flavoprotein 1, mitochondrial [KO:K03942] [EC:]
81728  Ndufv2; NADH dehydrogenase [ubiquinone] flavoprotein 2, mitochondrial precursor [KO:K03943] [EC:]
64539  Ndufv3; NADH dehydrogenase [ubiquinone] flavoprotein 3, mitochondrial isoform 2 [KO:K03944]
363441  Ndufa1; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1 [KO:K03945]
291660  Ndufa2; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 2 [KO:K03946]
691001  Ndufa3; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 3 [KO:K03947]
684509  NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 3 [KO:K03947]
681024  Ndufa4; cytochrome c oxidase subunit NDUFA4 [KO:K03948]
100362331  Ndufa4l2; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 4-like 2 [KO:K03948]
25488  Ndufa5; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 5 [KO:K03949]
315167  Ndufa6; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 6 [KO:K03950]
299643  Ndufa7; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 7 [KO:K03951]
296658  Ndufa8; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 8 [KO:K03952]
362440  Ndufa9; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9, mitochondrial [KO:K03953]
316632  Ndufa10l1; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 10-like [KO:K03954]
678759  Ndufa10; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10, mitochondrial precursor [KO:K03954]
293453  Ndufab1; acyl carrier protein, mitochondrial [KO:K03955]
301123  Ndufa11; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 11 [KO:K03956]
299739  Ndufa12; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 12 [KO:K11352]
100911483  Ndufa13; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 13 [KO:K11353]
362344  Ndufb2; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 2, mitochondrial [KO:K03958]
301427  Ndufb3; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 3 [KO:K03959]
288088  Ndufb4; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 4 [KO:K03960]
294964  Ndufb5; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 5, mitochondrial [KO:K03961]
297990  Ndufb6; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 6 [KO:K03962]
361385  Ndufb7; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 7 [KO:K03963]
293991  Ndufb8; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 8, mitochondrial [KO:K03964]
299954  Ndufb9; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 9 [KO:K03965]
681418  Ndufb10; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 10 [KO:K03966]
299310  Ndufb11; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 11, mitochondrial [KO:K11351]
301458  Ndufs1; NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial precursor [KO:K03934] [EC:]
289218  Ndufs2; NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, mitochondrial precursor [KO:K03935] [EC:]
295923  Ndufs3; NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial [KO:K03936] [EC:]
499529  Ndufs4; NADH dehydrogenase [ubiquinone] iron-sulfur protein 4, mitochondrial precursor [KO:K03937]
362588  Ndufs5; NADH dehydrogenase [ubiquinone] iron-sulfur protein 5 [KO:K03938]
100363268  NADH dehydrogenase [ubiquinone] iron-sulfur protein 5 [KO:K03938]
29478  Ndufs6; NADH dehydrogenase [ubiquinone] iron-sulfur protein 6, mitochondrial precursor [KO:K03939]
679739  NADH dehydrogenase [ubiquinone] iron-sulfur protein 6, mitochondrial [KO:K03939]
362837  Ndufs7; NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial [KO:K03940] [EC:]
293652  Ndufs8; NADH dehydrogenase [ubiquinone] iron-sulfur protein 8, mitochondrial [KO:K03941] [EC:]
689938  Ndufc1; NADH dehydrogenase [ubiquinone] 1 subunit C1, mitochondrial [KO:K03967]
293130  Ndufc2; NADH dehydrogenase [ubiquinone] 1 subunit C2 [KO:K03968]
157074  Sdha; succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial precursor [KO:K00234] [EC:]
298596  Sdhb; succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial precursor [KO:K00235] [EC:]
289217  Sdhc; succinate dehydrogenase cytochrome b560 subunit, mitochondrial [KO:K00236]
363061  Sdhd; succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial [KO:K00237]
291103  Uqcrfs1; cytochrome b-c1 complex subunit Rieske, mitochondrial [KO:K00411] [EC:]
26192  CYTB; cytochrome b [KO:K00412]
300047  Cyc1; cytochrome c-1 [KO:K00413]
301011  Uqcrc1; cytochrome b-c1 complex subunit 1, mitochondrial precursor [KO:K00414]
293448  Uqcrc2; cytochrome b-c1 complex subunit 2, mitochondrial precursor [KO:K00415]
366448  Uqcrh; cytochrome b-c1 complex subunit 6, mitochondrial [KO:K00416]
362897  Uqcrb; cytochrome b-c1 complex subunit 7 [KO:K00417]
497902  Uqcrq; cytochrome b-c1 complex subunit 8 [KO:K00418]
685322  Uqcr10; ubiquinol-cytochrome c reductase complex 7.2kDa protein [KO:K00419]
100361126  RGD2320734; cytochrome b-c1 complex subunit 9 [KO:K00419]
690848  Uqcr11; ubiquinol-cytochrome c reductase, complex III subunit XI [KO:K00420]
26204  COX3; cytochrome c oxidase subunit III [KO:K02262]
26195  COX1; cytochrome c oxidase subunit I [KO:K02256] [EC:]
26198  COX2; cytochrome c oxidase subunit II [KO:K02261]
84683  Cox4i2; cytochrome c oxidase subunit 4 isoform 2, mitochondrial isoform 2 precursor [KO:K02263]
29445  Cox4i1; cytochrome c oxidase subunit 4 isoform 1, mitochondrial precursor [KO:K02263]
252934  Cox5a; cytochrome c oxidase subunit 5A, mitochondrial precursor [KO:K02264]
94194  Cox5b; cytochrome c oxidase subunit 5B, mitochondrial precursor [KO:K02265]
25278  Cox6a2; cytochrome c oxidase subunit 6A2, mitochondrial precursor [KO:K02266]
25282  Cox6a1; cytochrome c oxidase subunit 6A1, mitochondrial precursor [KO:K02266]
688869  Cox6b1; cytochrome c oxidase subunit 6B1 [KO:K02267]
654441  Cox6b2; cytochrome c oxidase subunit 6B2 [KO:K02267]
54322  Cox6c; cytochrome c oxidase subunit 6C-2 [KO:K02268]
29507  Cox7a2; cytochrome c oxidase subunit 7A2, mitochondrial precursor [KO:K02270]
298762  Cox7a2l; cytochrome c oxidase subunit 7A2 like [KO:K02270]
688386  Cox7a2l2; cytochrome c oxidase subunit 7A2, mitochondrial [KO:K02270]
687508  cytochrome c oxidase subunit 7A1, mitochondrial isoform X2 [KO:K02270]
303393  Cox7b; cytochrome c oxidase subunit 7B, mitochondrial precursor [KO:K02271]
100361960  Cox7b2; cytochrome c oxidase subunit 7B, mitochondrial [KO:K02271]
100188937  Cox7c; cytochrome c oxidase subunit 7C, mitochondrial [KO:K02272]
25250  Cox8b; cytochrome c oxidase subunit 8B, mitochondrial precursor [KO:K02273]
360229  Cox8c; cytochrome c oxidase subunit 8C, mitochondrial [KO:K02273]
171335  Cox8a; cytochrome c oxidase subunit 8A, mitochondrial precursor [KO:K02273]
C00031  D-Glucose
C00162  Fatty acid
Naik A, Kosir R, Rozman D
Genomic aspects of NAFLD pathogenesis.
Genomics 102:84-95 (2013)
Malaguarnera M, Di Rosa M, Nicoletti F, Malaguarnera L
Molecular mechanisms involved in NAFLD progression.
J Mol Med (Berl) 87:679-95 (2009)
Seki E, Brenner DA, Karin M
A liver full of JNK: signaling in regulation of cell function and disease pathogenesis, and clinical approaches.
Gastroenterology 143:307-20 (2012)
Tilg H, Moschen AR
Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis.
Hepatology 52:1836-46 (2010)
Larter CZ, Farrell GC
Insulin resistance, adiponectin, cytokines in NASH: Which is the best target to treat?
J Hepatol 44:253-61 (2006)
Farrell GC, van Rooyen D, Gan L, Chitturi S
NASH is an Inflammatory Disorder: Pathogenic, Prognostic and Therapeutic Implications.
Gut Liver 6:149-71 (2012)
Shapiro H, Tehilla M, Attal-Singer J, Bruck R, Luzzatti R, Singer P
The therapeutic potential of long-chain omega-3 fatty acids in nonalcoholic fatty liver disease.
Clin Nutr 30:6-19 (2011)
Hotamisligil GS
Endoplasmic reticulum stress and the inflammatory basis of metabolic disease.
Cell 140:900-17 (2010)
Parekh S, Anania FA
Abnormal lipid and glucose metabolism in obesity: implications for nonalcoholic fatty liver disease.
Gastroenterology 132:2191-207 (2007)
Schattenberg JM, Singh R, Wang Y, Lefkowitch JH, Rigoli RM, Scherer PE, Czaja MJ
JNK1 but not JNK2 promotes the development of steatohepatitis in mice.
Hepatology 43:163-72 (2006)
Leung TM, Nieto N
CYP2E1 and oxidant stress in alcoholic and non-alcoholic fatty liver disease.
J Hepatol 58:395-8 (2013)
Zafrani ES
Non-alcoholic fatty liver disease: an emerging pathological spectrum.
Virchows Arch 444:3-12 (2004)
Feldstein AE, Canbay A, Angulo P, Taniai M, Burgart LJ, Lindor KD, Gores GJ
Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis.
Gastroenterology 125:437-43 (2003)
Begriche K, Igoudjil A, Pessayre D, Fromenty B
Mitochondrial dysfunction in NASH: causes, consequences and possible means to prevent it.
Mitochondrion 6:1-28 (2006)
Leonarduzzi G, Scavazza A, Biasi F, Chiarpotto E, Camandola S, Vogel S, Dargel R, Poli G
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.
FASEB J 11:851-7 (1997)
Malhi H, Kaufman RJ
Endoplasmic reticulum stress in liver disease.
J Hepatol 54:795-809 (2011)
Mantena SK, King AL, Andringa KK, Eccleston HB, Bailey SM
Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases.
Free Radic Biol Med 44:1259-72 (2008)
Serviddio G, Sastre J, Bellanti F, Vina J, Vendemiale G, Altomare E
Mitochondrial involvement in non-alcoholic steatohepatitis.
Mol Aspects Med 29:22-35 (2008)
Begriche K, Massart J, Robin MA, Bonnet F, Fromenty B
Mitochondrial adaptations and dysfunctions in nonalcoholic fatty liver disease.
Hepatology 58:1497-507 (2013)
rno00061  Fatty acid biosynthesis
rno00190  Oxidative phosphorylation
rno03320  PPAR signaling pathway
rno04141  Protein processing in endoplasmic reticulum
rno04151  PI3K-Akt signaling pathway
rno04210  Apoptosis
rno04668  TNF signaling pathway
rno04920  Adipocytokine signaling pathway
rno04930  Type II diabetes mellitus
KO pathway

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