KEGG   PATHWAY: afz04936
Entry
afz04936                    Pathway                                
Name
Alcoholic liver disease - Antechinus flavipes (yellow-footed antechinus)
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
afz04936  Alcoholic liver disease
afz04936

Organism
Antechinus flavipes (yellow-footed antechinus) [GN:afz]
Gene
127561087  complement C2 [KO:K01332] [EC:3.4.21.43]
127561083  complement C4-like [KO:K03989]
127544864  complement C3 [KO:K03990]
127564812  C3a anaphylatoxin chemotactic receptor [KO:K04009]
127550531  complement C5 [KO:K03994]
127556252  C5a anaphylatoxin chemotactic receptor 1 isoform X1 [KO:K04010]
127550426  lipopolysaccharide-binding protein-like [KO:K05399]
127550003  monocyte differentiation antigen CD14 [KO:K04391]
127543760  lymphocyte antigen 96 isoform X1 [KO:K05400]
127550519  toll-like receptor 4 [KO:K10160]
127554825  toll/interleukin-1 receptor domain-containing adapter protein isoform X1 [KO:K05403]
127550351  myeloid differentiation primary response protein MyD88 [KO:K04729]
127538287  interleukin-1 receptor-associated kinase 4 isoform X1 [KO:K04733] [EC:2.7.11.1]
127542305  interleukin-1 receptor-associated kinase 1 [KO:K04730] [EC:2.7.11.1]
127542124  LOW QUALITY PROTEIN: TNF receptor-associated factor 6 [KO:K03175] [EC:2.3.2.27]
127538308  TGF-beta-activated kinase 1 and MAP3K7-binding protein 1 [KO:K04403]
127562312  TGF-beta-activated kinase 1 and MAP3K7-binding protein 2 [KO:K04404]
127562007  mitogen-activated protein kinase kinase kinase 7 isoform X1 [KO:K04427] [EC:2.7.11.25]
127548272  inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
127542289  NF-kappa-B essential modulator isoform X1 [KO:K07210]
127549751  NF-kappa-B inhibitor alpha [KO:K04734]
127540746  transcription factor p65 isoform X1 [KO:K04735]
127541094  nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
127559172  tumor necrosis factor [KO:K03156]
127547601  interleukin-1 beta [KO:K04519]
127557721  interleukin-12 subunit alpha [KO:K05406]
127546715  interleukin-12 subunit beta [KO:K05425]
127540720  interleukin-8 [KO:K10030]
127541566  TIR domain-containing adapter molecule 1 [KO:K05842]
127549887  TNF receptor-associated factor 3 [KO:K03174]
127562632  inhibitor of nuclear factor kappa-B kinase subunit epsilon [KO:K07211] [EC:2.7.11.10]
127539419  serine/threonine-protein kinase TBK1 [KO:K05410] [EC:2.7.11.10]
127556561  interferon regulatory factor 3 [KO:K05411]
127544839  interferon tau-like [KO:K05414]
127544846  interferon tau-like [KO:K05414]
127552476  interferon alpha-16-like [KO:K05414]
127552756  interferon alpha-1-like [KO:K05414]
127552856  interferon omega-1-like [KO:K05414]
127552925  interferon beta-like [KO:K05415]
127561457  interleukin-17A [KO:K05489]
127564850  interleukin-17 receptor A [KO:K05164]
127551821  interleukin-17 receptor C isoform X1 [KO:K05166]
127540718  permeability factor 2-like [KO:K05505]
127540719  permeability factor 2-like [KO:K05505]
127562897  tumor necrosis factor ligand superfamily member 6 isoform X1 [KO:K04389]
127552171  LOW QUALITY PROTEIN: tumor necrosis factor receptor superfamily member 6 [KO:K04390]
127540264  FAS-associated death domain protein [KO:K02373]
127538963  tumor necrosis factor receptor superfamily member 1A [KO:K03158]
127547929  tumor necrosis factor receptor type 1-associated DEATH domain protein [KO:K03171]
127553228  caspase-8 isoform X1 [KO:K04398] [EC:3.4.22.61]
127542048  caspase-3 [KO:K02187] [EC:3.4.22.56]
127544228  receptor-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K02861] [EC:2.7.11.1]
127553936  TGF-beta-activated kinase 1 and MAP3K7-binding protein 3 [KO:K12793]
127562168  sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
127560599  fatty acid synthase [KO:K00665] [EC:2.3.1.85]
127559918  acetyl-CoA carboxylase 1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
127539913  stearoyl-CoA desaturase 5 isoform X1 [KO:K00507] [EC:1.14.19.1]
127550394  phosphatidate phosphatase LPIN3 isoform X1 [KO:K15728] [EC:3.1.3.4]
127543985  phosphatidate phosphatase LPIN2 isoform X1 [KO:K15728] [EC:3.1.3.4]
127547312  phosphatidate phosphatase LPIN1 isoform X1 [KO:K15728] [EC:3.1.3.4]
127552112  NAD-dependent protein deacetylase sirtuin-1 [KO:K11411] [EC:2.3.1.286]
127563522  transformer-2 protein homolog beta isoform X1 [KO:K12897]
127542613  transformer-2 protein homolog beta-like [KO:K12897]
127539325  transformer-2 protein homolog alpha [KO:K12897]
127558613  adiponectin [KO:K07296]
127562707  adiponectin receptor protein 1 [KO:K07297]
127538949  adiponectin receptor protein 2 [KO:K07297]
127545450  calcium/calmodulin-dependent protein kinase kinase 2 isoform X1 [KO:K07359] [EC:2.7.11.17]
127563258  5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
127556825  5'-AMP-activated protein kinase catalytic subunit alpha-1 [KO:K07198] [EC:2.7.11.31]
127545541  LOW QUALITY PROTEIN: 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
127559188  5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
127564149  5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
127538054  5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
127553096  5'-AMP-activated protein kinase subunit gamma-3 isoform X1 [KO:K07200]
127555224  forkhead box protein O1 [KO:K07201]
127562063  forkhead box protein O3 [KO:K09408]
127539643  peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
127538966  peroxisome proliferator-activated receptor alpha [KO:K07294]
127540255  carnitine O-palmitoyltransferase 1, liver isoform [KO:K08765] [EC:2.3.1.21]
127558293  very long-chain specific acyl-CoA dehydrogenase, mitochondrial-like [KO:K09479] [EC:1.3.8.9]
127560911  very long-chain specific acyl-CoA dehydrogenase, mitochondrial [KO:K09479] [EC:1.3.8.9]
127563135  medium-chain specific acyl-CoA dehydrogenase, mitochondrial [KO:K00249] [EC:1.3.8.7]
127541497  peroxisomal acyl-coenzyme A oxidase 3 [KO:K00232] [EC:1.3.3.6]
127560452  peroxisomal acyl-coenzyme A oxidase 1 isoform X1 [KO:K00232] [EC:1.3.3.6]
127547474  fatty acid-binding protein, liver [KO:K08750]
127541241  all-trans-retinol dehydrogenase [NAD(+)] ADH7-like isoform X1 [KO:K13951] [EC:1.1.1.1]
127541243  alcohol dehydrogenase E chain-like [KO:K13951] [EC:1.1.1.1]
127541244  all-trans-retinol dehydrogenase [NAD(+)] ADH7 [KO:K13951] [EC:1.1.1.1]
127541246  all-trans-retinol dehydrogenase [NAD(+)] ADH7-like [KO:K13951] [EC:1.1.1.1]
127541245  alcohol dehydrogenase class-3 [KO:K00121] [EC:1.1.1.284 1.1.1.1]
127556545  aldehyde dehydrogenase family 16 member A1 [KO:K00128] [EC:1.2.1.3]
127558784  aldehyde dehydrogenase family 3 member A2 isoform X1 [KO:K00128] [EC:1.2.1.3]
127545479  aldehyde dehydrogenase, mitochondrial [KO:K00128] [EC:1.2.1.3]
127560856  aldehyde dehydrogenase X, mitochondrial isoform X1 [KO:K00128] [EC:1.2.1.3]
127560239  alpha-aminoadipic semialdehyde dehydrogenase [KO:K14085] [EC:1.2.1.31 1.2.1.8 1.2.1.3]
127562963  4-trimethylaminobutyraldehyde dehydrogenase [KO:K00149] [EC:1.2.1.47 1.2.1.3]
127546978  cytochrome P450 2E1-like [KO:K07415] [EC:1.14.14.-]
127546992  cytochrome P450 2C42-like [KO:K07415] [EC:1.14.14.-]
127545590  acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
127548679  malonyl-CoA decarboxylase, mitochondrial [KO:K01578] [EC:4.1.1.9]
127538809  carnitine O-palmitoyltransferase 1, muscle isoform isoform X1 [KO:K19523] [EC:2.3.1.21]
127556546  carnitine O-palmitoyltransferase 1, brain isoform [KO:K19524] [EC:2.3.1.21]
127555167  NADPH oxidase 4 isoform X1 [KO:K21423] [EC:1.6.3.-]
127549861  RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
127556193  RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
127559596  RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
127554112  glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
127539437  catenin beta-1 isoform X1 [KO:K02105]
127549825  transcription factor 7 isoform X1 [KO:K02620]
127547432  transcription factor 7-like 1 [KO:K04490]
127551589  transcription factor 7-like 2 isoform X1 [KO:K04491]
127539946  lymphoid enhancer-binding factor 1 isoform X1 [KO:K04492]
127539835  G1/S-specific cyclin-D1 [KO:K04503]
127562250  mitogen-activated protein kinase kinase kinase 5 [KO:K04426] [EC:2.7.11.25]
127560734  dual specificity mitogen-activated protein kinase kinase 4 isoform X1 [KO:K04430] [EC:2.7.12.2]
127545314  dual specificity mitogen-activated protein kinase kinase 7 isoform X1 [KO:K04431] [EC:2.7.12.2]
127542137  mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
127550306  mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
127551815  mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
127563289  dual specificity mitogen-activated protein kinase kinase 3 isoform X1 [KO:K04432] [EC:2.7.12.2]
127560548  dual specificity mitogen-activated protein kinase kinase 6 [KO:K04433] [EC:2.7.12.2]
127538834  mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
127538838  mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
127561225  mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
127561226  mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
127560369  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
afz00061  Fatty acid biosynthesis
afz00071  Fatty acid degradation
afz01040  Biosynthesis of unsaturated fatty acids
afz03040  Spliceosome
afz04010  MAPK signaling pathway
afz04064  NF-kappa B signaling pathway
afz04152  AMPK signaling pathway
afz04210  Apoptosis
afz04310  Wnt signaling pathway
afz04610  Complement and coagulation cascades
afz04620  Toll-like receptor signaling pathway
afz04657  IL-17 signaling pathway
afz04668  TNF signaling pathway
afz04920  Adipocytokine signaling pathway
afz05034  Alcoholism
afz05225  Hepatocellular carcinoma
KO pathway
ko04936   
LinkDB

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