KEGG   PATHWAY: ptg04936
Entry
ptg04936                    Pathway                                
Name
Alcoholic liver disease - Panthera tigris altaica (Amur tiger)
Description
Alcoholic liver disease (ALD) refers to the damages to the liver and its functions due to alcohol overconsumption. It ranges from simple steatosis to steatohepatitis, cirrhosis, and even hepatocellular carcinoma. Alcohol consumption promotes liver inflammation by increasing the translocation of gut-derived endotoxins to the portal circulation and activating Kupffer cells to produce TNF-alpha through the LPS/Toll like receptor (TLR) 4 pathways. TNF-alpha induces hepatocellular damage. When alcohol intake is chronic and heavy, steatosis is caused via generation of acetaldehyde, reactive oxygen species (ROS) and ER stress. ROS inhibits key hepatic transcriptional regulators such as AMP-activated kinase (AMPK) and peroxisome proliferator-activated receptor alpha (PPAR-alpha), which are responsible for fatty acid oxidation and export via ACC and CPT-1. The blockade of AMPK also leads to overexpression of SREBP-1, resulting in an increase of de novo lipogenesis. Moreover, excessive intracellular ROS production induced by ethanol and its metabolite have a critical role in ethanol-induced apoptosis, which may be the critical process in the exacerbation of ALD. It is inferred that the apoptotic signal derived from ROS that was produced by NOX, is mainly transduced through the JNK and p38 MAPK pathways.
Class
Human Diseases; Endocrine and metabolic disease
Pathway map
ptg04936  Alcoholic liver disease
ptg04936

Organism
Panthera tigris altaica (Amur tiger) [GN:ptg]
Gene
102971698  C1QA; complement C1q A chain [KO:K03986]
102972468  C1QB; complement C1q B chain [KO:K03987]
102972183  C1QC; complement C1q C chain [KO:K03988]
102969252  C2; complement C2 [KO:K01332] [EC:3.4.21.43]
102967020  C4A; complement C4-A [KO:K03989]
102951325  complement C3-like [KO:K03990]
102968028  C3; complement C3 [KO:K03990]
102968326  complement C3-like [KO:K03990]
102967243  C3AR1; complement C3a receptor 1 [KO:K04009]
102962969  complement C5-like [KO:K03994]
102962094  C5AR1; C5a anaphylatoxin chemotactic receptor 1 [KO:K04010]
102948801  LBP; lipopolysaccharide binding protein [KO:K05399]
107179209  lipopolysaccharide-binding protein-like [KO:K05399]
102956253  CD14; CD14 molecule [KO:K04391]
102958453  LY96; lymphocyte antigen 96 [KO:K05400]
102959529  TLR4; toll like receptor 4 [KO:K10160]
102970131  TIRAP; TIR domain containing adaptor protein [KO:K05403]
102952059  MYD88; myeloid differentiation primary response 88 [KO:K04729]
102962570  IRAK4; interleukin 1 receptor associated kinase 4 [KO:K04733] [EC:2.7.11.1]
102960157  TRAF6; TNF receptor associated factor 6 [KO:K03175] [EC:2.3.2.27]
102950874  TAB1; TGF-beta activated kinase 1 (MAP3K7) binding protein 1 [KO:K04403]
102959790  TAB2; TGF-beta activated kinase 1/MAP3K7 binding protein 2 [KO:K04404]
102963341  MAP3K7; mitogen-activated protein kinase kinase kinase 7 [KO:K04427] [EC:2.7.11.25]
102949289  CHUK; conserved helix-loop-helix ubiquitous kinase [KO:K04467] [EC:2.7.11.10]
102963734  IKBKB; inhibitor of nuclear factor kappa B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
102956127  NFKBIA; NFKB inhibitor alpha [KO:K04734]
102951132  RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735]
102964232  NFKB1; nuclear factor kappa B subunit 1 [KO:K02580]
102958919  TNF; tumor necrosis factor [KO:K03156]
102951272  IL1B; interleukin 1 beta [KO:K04519]
102968780  IL6; interleukin 6 [KO:K05405]
102971802  IL12A; interleukin 12A [KO:K05406]
102959546  IL12B; interleukin 12B [KO:K05425]
102953898  interleukin-8-like [KO:K10030]
102953024  IL8; interleukin-8 [KO:K10030]
102951327  TICAM1; toll like receptor adaptor molecule 1 [KO:K05842]
102952767  TRAF3; TNF receptor associated factor 3 [KO:K03174]
102963614  IKBKE; inhibitor of nuclear factor kappa B kinase subunit epsilon [KO:K07211] [EC:2.7.11.10]
102960158  TBK1; TANK binding kinase 1 [KO:K05410] [EC:2.7.11.10]
102956602  IRF3; interferon regulatory factor 3 [KO:K05411]
102956750  interferon alpha-2-like [KO:K05414]
102960421  IFNB1; interferon beta 1 [KO:K05415]
102972536  IL17A; interleukin 17A [KO:K05489]
102955272  IL17RA; interleukin 17 receptor A [KO:K05164]
102956141  IL17RC; interleukin 17 receptor C [KO:K05166]
102953222  FASLG; Fas ligand [KO:K04389]
102958442  FAS; Fas cell surface death receptor [KO:K04390]
102956793  TNFRSF1A; TNF receptor superfamily member 1A [KO:K03158]
102968597  TRADD; TNFRSF1A associated via death domain [KO:K03171]
102962460  CASP8; caspase 8 [KO:K04398] [EC:3.4.22.61]
102954729  CASP3; caspase 3 [KO:K02187] [EC:3.4.22.56]
102964459  RIPK1; receptor interacting serine/threonine kinase 1 [KO:K02861] [EC:2.7.11.1]
102964345  TAB3; TGF-beta activated kinase 1/MAP3K7 binding protein 3 [KO:K12793]
102967397  SREBF1; sterol regulatory element binding transcription factor 1 [KO:K07197]
102956933  FASN; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
102954149  ACACA; acetyl-CoA carboxylase alpha [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
102966019  SCD5; stearoyl-CoA desaturase 5 [KO:K00507] [EC:1.14.19.1]
102950164  SCD; stearoyl-CoA desaturase [KO:K00507] [EC:1.14.19.1]
102953367  LPIN3; lipin 3 [KO:K15728] [EC:3.1.3.4]
102950762  LPIN1; lipin 1 [KO:K15728] [EC:3.1.3.4]
102972500  LPIN2; lipin 2 [KO:K15728] [EC:3.1.3.4]
102963908  SIRT1; sirtuin 1 [KO:K11411] [EC:2.3.1.286]
102963760  TRA2B; transformer 2 beta homolog (Drosophila) [KO:K12897]
102964549  TRA2A; transformer 2 alpha homolog [KO:K12897]
102960062  ADIPOQ; adiponectin, C1Q and collagen domain containing [KO:K07296]
102957726  ADIPOR2; adiponectin receptor 2 [KO:K07297]
102951965  ADIPOR1; adiponectin receptor 1 [KO:K07297]
102971870  CAMKK2; calcium/calmodulin dependent protein kinase kinase 2 [KO:K07359] [EC:2.7.11.17]
102970831  PRKAA2; protein kinase AMP-activated catalytic subunit alpha 2 [KO:K07198] [EC:2.7.11.31]
102956343  PRKAA1; protein kinase AMP-activated catalytic subunit alpha 1 [KO:K07198] [EC:2.7.11.31]
102972403  PRKAB2; protein kinase AMP-activated non-catalytic subunit beta 2 [KO:K07199]
102952112  PRKAB1; protein kinase AMP-activated non-catalytic subunit beta 1 [KO:K07199]
102951896  PRKAG1; protein kinase AMP-activated non-catalytic subunit gamma 1 [KO:K07200]
102960269  PRKAG2; protein kinase AMP-activated non-catalytic subunit gamma 2 [KO:K07200]
102959115  PRKAG3; protein kinase AMP-activated non-catalytic subunit gamma 3 [KO:K07200]
102969147  FOXO1; forkhead box O1 [KO:K07201]
102961930  FOXO3; forkhead box O3 [KO:K09408]
102972614  PPARGC1A; PPARG coactivator 1 alpha [KO:K07202]
102971837  PPARA; peroxisome proliferator activated receptor alpha [KO:K07294]
102960681  CPT1A; carnitine palmitoyltransferase 1A [KO:K08765] [EC:2.3.1.21]
102968012  ACADVL; acyl-CoA dehydrogenase, very long chain [KO:K09479] [EC:1.3.8.9]
102961751  ACADM; acyl-CoA dehydrogenase, C-4 to C-12 straight chain [KO:K00249] [EC:1.3.8.7]
102949456  ACOX3; acyl-CoA oxidase 3, pristanoyl [KO:K00232] [EC:1.3.3.6]
102964654  ACOX1; acyl-CoA oxidase 1 [KO:K00232] [EC:1.3.3.6]
102970523  FABP1; fatty acid binding protein 1 [KO:K08750]
102970414  alcohol dehydrogenase E chain [KO:K13951] [EC:1.1.1.1]
102971197  ADH4; alcohol dehydrogenase 4 (class II), pi polypeptide [KO:K13980] [EC:1.1.1.1]
102971488  ADH5; alcohol dehydrogenase 5 (class III), chi polypeptide [KO:K00121] [EC:1.1.1.284 1.1.1.1]
102956541  ALDH2; aldehyde dehydrogenase 2 family (mitochondrial) [KO:K00128] [EC:1.2.1.3]
102963091  ALDH3A2; aldehyde dehydrogenase 3 family member A2 [KO:K00128] [EC:1.2.1.3]
102955542  ALDH1B1; aldehyde dehydrogenase 1 family member B1 [KO:K00128] [EC:1.2.1.3]
102954203  ALDH16A1; aldehyde dehydrogenase 16 family member A1 [KO:K00128] [EC:1.2.1.3]
102951788  ALDH7A1; aldehyde dehydrogenase 7 family member A1 [KO:K14085] [EC:1.2.1.31 1.2.1.8 1.2.1.3]
102951347  ALDH9A1; aldehyde dehydrogenase 9 family member A1 [KO:K00149] [EC:1.2.1.47 1.2.1.3]
102969051  cytochrome P450 2E1 [KO:K07415] [EC:1.14.14.-]
102963315  ACACB; acetyl-CoA carboxylase beta [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
102957973  MLYCD; malonyl-CoA decarboxylase [KO:K01578] [EC:4.1.1.9]
102952682  CPT1B; carnitine palmitoyltransferase 1B [KO:K19523] [EC:2.3.1.21]
102969205  CPT1C; carnitine palmitoyltransferase 1C [KO:K19524] [EC:2.3.1.21]
102952905  NOX4; NADPH oxidase 4 [KO:K21423] [EC:1.6.3.-]
102952603  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]
102954757  AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1]
102961382  GSK3B; glycogen synthase kinase 3 beta [KO:K03083] [EC:2.7.11.26]
102959570  CTNNB1; catenin beta 1 [KO:K02105]
102957988  TCF7; transcription factor 7 (T-cell specific, HMG-box) [KO:K02620]
102958078  TCF7L1; transcription factor 7 like 1 [KO:K04490]
102961321  TCF7L2; transcription factor 7 like 2 [KO:K04491]
102970026  LEF1; lymphoid enhancer binding factor 1 [KO:K04492]
102959906  CCND1; cyclin D1 [KO:K04503]
102960317  MAP3K5; mitogen-activated protein kinase kinase kinase 5 [KO:K04426] [EC:2.7.11.25]
102966812  MAP2K4; mitogen-activated protein kinase kinase 4 [KO:K04430] [EC:2.7.12.2]
102949140  MAP2K7; mitogen-activated protein kinase kinase 7 [KO:K04431] [EC:2.7.12.2]
102959159  MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
102950880  MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
102963096  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
102949954  MAP2K3; mitogen-activated protein kinase kinase 3 [KO:K04432] [EC:2.7.12.2]
102966485  MAP2K6; mitogen-activated protein kinase kinase 6 [KO:K04433] [EC:2.7.12.2]
102968191  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
102960306  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
102960590  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
102968482  MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
102964388  MAP3K14; mitogen-activated protein kinase kinase kinase 14 [KO:K04466] [EC:2.7.11.25]
Compound
C00003  NAD+
C00005  NADPH
C00006  NADP+
C00024  Acetyl-CoA
C00033  Acetate
C00040  Acyl-CoA
C00076  Calcium cation
C00083  Malonyl-CoA
C00084  Acetaldehyde
C00469  Ethanol
C22381  Reactive oxygen species
Reference
PMID:25782093
  Authors
Louvet A, Mathurin P
  Title
Alcoholic liver disease: mechanisms of injury and targeted treatment.
  Journal
Nat Rev Gastroenterol Hepatol 12:231-42 (2015)
DOI:10.1038/nrgastro.2015.35
Reference
PMID:21920463
  Authors
Gao B, Bataller R
  Title
Alcoholic liver disease: pathogenesis and new therapeutic targets.
  Journal
Gastroenterology 141:1572-85 (2011)
DOI:10.1053/j.gastro.2011.09.002
Reference
PMID:28134813
  Authors
Magdaleno F, Blajszczak CC, Nieto N
  Title
Key Events Participating in the Pathogenesis of Alcoholic Liver Disease.
  Journal
Biomolecules 7:E9 (2017)
DOI:10.3390/biom7010009
Reference
PMID:19553649
  Authors
Lucey MR, Mathurin P, Morgan TR
  Title
Alcoholic hepatitis.
  Journal
N Engl J Med 360:2758-69 (2009)
DOI:10.1056/NEJMra0805786
Reference
PMID:26919968
  Authors
Nagy LE, Ding WX, Cresci G, Saikia P, Shah VH
  Title
Linking Pathogenic Mechanisms of Alcoholic Liver Disease With Clinical Phenotypes.
  Journal
Gastroenterology 150:1756-68 (2016)
DOI:10.1053/j.gastro.2016.02.035
Reference
PMID:25009376
  Authors
Fujii H, Kawada N
  Title
Fibrogenesis in alcoholic liver disease.
  Journal
World J Gastroenterol 20:8048-54 (2014)
DOI:10.3748/wjg.v20.i25.8048
Reference
PMID:26755857
  Authors
Kim MS, Ong M, Qu X
  Title
Optimal management for alcoholic liver disease: Conventional medications, natural therapy or combination?
  Journal
World J Gastroenterol 22:8-23 (2016)
DOI:10.3748/wjg.v22.i1.8
Reference
PMID:15194557
  Authors
You M, Crabb DW
  Title
Recent advances in alcoholic liver disease II. Minireview: molecular mechanisms of alcoholic fatty liver.
  Journal
Am J Physiol Gastrointest Liver Physiol 287:G1-6 (2004)
DOI:10.1152/ajpgi.00056.2004
Reference
PMID:26695748
  Authors
Nagy LE
  Title
The Role of Innate Immunity in Alcoholic Liver Disease.
  Journal
Alcohol Res 37:237-50 (2015)
Reference
PMID:21252049
  Authors
Gao B, Seki E, Brenner DA, Friedman S, Cohen JI, Nagy L, Szabo G, Zakhari S
  Title
Innate immunity in alcoholic liver disease.
  Journal
Am J Physiol Gastrointest Liver Physiol 300:G516-25 (2011)
DOI:10.1152/ajpgi.00537.2010
Reference
PMID:22524187
  Authors
Wang HJ, Gao B, Zakhari S, Nagy LE
  Title
Inflammation in alcoholic liver disease.
  Journal
Annu Rev Nutr 32:343-68 (2012)
DOI:10.1146/annurev-nutr-072610-145138
Reference
PMID:29597356
  Authors
McCullough RL, McMullen MR, Sheehan MM, Poulsen KL, Roychowdhury S, Chiang DJ, Pritchard MT, Caballeria J, Nagy LE
  Title
Complement Factor D protects mice from ethanol-induced inflammation and liver injury.
  Journal
Am J Physiol Gastrointest Liver Physiol 315:G66-G79 (2018)
DOI:10.1152/ajpgi.00334.2017
Reference
PMID:24385684
  Authors
Kawaratani H, Tsujimoto T, Douhara A, Takaya H, Moriya K, Namisaki T, Noguchi R, Yoshiji H, Fujimoto M, Fukui H
  Title
The effect of inflammatory cytokines in alcoholic liver disease.
  Journal
Mediators Inflamm 2013:495156 (2013)
DOI:10.1155/2013/495156
Reference
PMID:20238398
  Authors
Szabo G, Bala S
  Title
Alcoholic liver disease and the gut-liver axis.
  Journal
World J Gastroenterol 16:1321-9 (2010)
DOI:10.3748/wjg.v16.i11.1321
Reference
PMID:28627645
  Authors
Kawaratani H, Moriya K, Namisaki T, Uejima M, Kitade M, Takeda K, Okura Y, Kaji K, Takaya H, Nishimura N, Sato S, Sawada Y, Seki K, Kubo T, Mitoro A, Yamao J, Yoshiji H
  Title
Therapeutic strategies for alcoholic liver disease: Focusing on inflammation and fibrosis (Review).
  Journal
Int J Mol Med 40:263-270 (2017)
DOI:10.3892/ijmm.2017.3015
Reference
PMID:23855294
  Authors
Roh YS, Seki E
  Title
Toll-like receptors in alcoholic liver disease, non-alcoholic steatohepatitis and carcinogenesis.
  Journal
J Gastroenterol Hepatol 28 Suppl 1:38-42 (2013)
DOI:10.1111/jgh.12019
Reference
PMID:18709650
  Authors
Rogers CQ, Ajmo JM, You M
  Title
Adiponectin and alcoholic fatty liver disease.
  Journal
IUBMB Life 60:790-7 (2008)
DOI:10.1002/iub.124
Reference
PMID:26278388
  Authors
You M, Jogasuria A, Lee K, Wu J, Zhang Y, Lee YK, Sadana P
  Title
Signal Transduction Mechanisms of Alcoholic Fatty Liver Disease: Emer ging Role of Lipin-1.
  Journal
Curr Mol Pharmacol 10:226-236 (2017)
DOI:10.2174/1874467208666150817112109
Reference
PMID:26005675
  Authors
You M, Jogasuria A, Taylor C, Wu J
  Title
Sirtuin 1 signaling and alcoholic fatty liver disease.
  Journal
Hepatobiliary Surg Nutr 4:88-100 (2015)
DOI:10.3978/j.issn.2304-3881.2014.12.06
Reference
PMID:33162823
  Authors
Ren R, Wang Z, Wu M, Wang H
  Title
Emerging Roles of SIRT1 in Alcoholic Liver Disease.
  Journal
Int J Biol Sci 16:3174-3183 (2020)
DOI:10.7150/ijbs.49535
Reference
PMID:19032584
  Authors
Purohit V, Gao B, Song BJ
  Title
Molecular mechanisms of alcoholic fatty liver.
  Journal
Alcohol Clin Exp Res 33:191-205 (2009)
DOI:10.1111/j.1530-0277.2008.00827.x
Reference
PMID:34071962
  Authors
Hyun J, Han J, Lee C, Yoon M, Jung Y
  Title
Pathophysiological Aspects of Alcohol Metabolism in the Liver.
  Journal
Int J Mol Sci 22:5717 (2021)
DOI:10.3390/ijms22115717
Reference
PMID:24297186
  Authors
Combs TP, Marliss EB
  Title
Adiponectin signaling in the liver.
  Journal
Rev Endocr Metab Disord 15:137-47 (2014)
DOI:10.1007/s11154-013-9280-6
Reference
PMID:25548474
  Authors
Ceni E, Mello T, Galli A
  Title
Pathogenesis of alcoholic liver disease: role of oxidative metabolism.
  Journal
World J Gastroenterol 20:17756-72 (2014)
DOI:10.3748/wjg.v20.i47.17756
Reference
PMID:31159489
  Authors
Kong LZ, Chandimali N, Han YH, Lee DH, Kim JS, Kim SU, Kim TD, Jeong DK, Sun HN, Lee DS, Kwon T
  Title
Pathogenesis, Early Diagnosis, and Therapeutic Management of Alcoholic Liver Disease.
  Journal
Int J Mol Sci 20:E2712 (2019)
DOI:10.3390/ijms20112712
Reference
PMID:31214376
  Authors
Ohashi K, Pimienta M, Seki E
  Title
Alcoholic liver disease: A current molecular and clinical perspective.
  Journal
Liver Res 2:161-172 (2018)
DOI:10.1016/j.livres.2018.11.002
Reference
PMID:30658725
  Authors
You M, Arteel GE
  Title
Effect of ethanol on lipid metabolism.
  Journal
J Hepatol 70:237-248 (2019)
DOI:10.1016/j.jhep.2018.10.037
Reference
PMID:25595739
  Authors
Bi L, Jiang Z, Zhou J
  Title
The role of lipin-1 in the pathogenesis of alcoholic fatty liver.
  Journal
Alcohol Alcohol 50:146-51 (2015)
DOI:10.1093/alcalc/agu102
Reference
PMID:31263795
  Authors
Ali H, Assiri MA, Shearn CT, Fritz KS
  Title
Lipid peroxidation derived reactive aldehydes in alcoholic liver disease.
  Journal
Curr Opin Toxicol 13:110-117 (2019)
DOI:10.1016/j.cotox.2018.10.003
Reference
PMID:24262277
  Authors
Yin H, Hu M, Liang X, Ajmo JM, Li X, Bataller R, Odena G, Stevens SM Jr, You M
  Title
Deletion of SIRT1 from hepatocytes in mice disrupts lipin-1 signaling and aggravates alcoholic fatty liver.
  Journal
Gastroenterology 146:801-11 (2014)
DOI:10.1053/j.gastro.2013.11.008
Reference
PMID:22110053
  Authors
Stickel F, Hampe J
  Title
Genetic determinants of alcoholic liver disease.
  Journal
Gut 61:150-9 (2012)
DOI:10.1136/gutjnl-2011-301239
Reference
PMID:29336467
  Authors
Yang CF, Zhong YJ, Ma Z, Li L, Shi L, Chen L, Li C, Wu D, Chen Q, Li YW
  Title
NOX4/ROS mediate ethanolinduced apoptosis via MAPK signal pathway in L02 cells.
  Journal
Int J Mol Med 41:2306-2316 (2018)
DOI:10.3892/ijmm.2018.3390
Related
pathway
ptg00061  Fatty acid biosynthesis
ptg00071  Fatty acid degradation
ptg01040  Biosynthesis of unsaturated fatty acids
ptg03040  Spliceosome
ptg04010  MAPK signaling pathway
ptg04064  NF-kappa B signaling pathway
ptg04152  AMPK signaling pathway
ptg04210  Apoptosis
ptg04310  Wnt signaling pathway
ptg04610  Complement and coagulation cascades
ptg04620  Toll-like receptor signaling pathway
ptg04657  IL-17 signaling pathway
ptg04668  TNF signaling pathway
ptg04920  Adipocytokine signaling pathway
ptg05034  Alcoholism
ptg05225  Hepatocellular carcinoma
KO pathway
ko04936   
LinkDB

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