Entry
Name
Alcoholic liver disease - Homo sapiens (human)
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
BRITE hierarchy
Pathway map
Ortholog table
Disease
H02516 Alcoholic liver disease
Drug
Organism
Homo sapiens (human) [GN:
hsa ]
Gene
720 C4A; complement C4A (Chido/Rodgers blood group) [KO:K03989 ]
721 C4B; complement C4B (Chido/Rodgers blood group) [KO:K03989 ]
719 C3AR1; complement C3a receptor 1 [KO:K04009 ]
728 C5AR1; complement C5a receptor 1 [KO:K04010 ]
3929 LBP; lipopolysaccharide binding protein [KO:K05399 ]
114609 TIRAP; TIR domain containing adaptor protein [KO:K05403 ]
4615 MYD88; MYD88 innate immune signal transduction adaptor [KO:K04729 ]
10454 TAB1; TGF-beta activated kinase 1 (MAP3K7) binding protein 1 [KO:K04403 ]
23118 TAB2; TGF-beta activated kinase 1 (MAP3K7) binding protein 2 [KO:K04404 ]
1147 CHUK; component of inhibitor of nuclear factor kappa B kinase complex [KO:K04467 ] [EC:2.7.11.10 ]
8517 IKBKG; inhibitor of nuclear factor kappa B kinase regulatory subunit gamma [KO:K07210 ]
5970 RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735 ]
4790 NFKB1; nuclear factor kappa B subunit 1 [KO:K02580 ]
3576 CXCL8; C-X-C motif chemokine ligand 8 [KO:K10030 ]
148022 TICAM1; TIR domain containing adaptor molecule 1 [KO:K05842 ]
7187 TRAF3; TNF receptor associated factor 3 [KO:K03174 ]
9641 IKBKE; inhibitor of nuclear factor kappa B kinase subunit epsilon [KO:K07211 ] [EC:2.7.11.10 ]
3661 IRF3; interferon regulatory factor 3 [KO:K05411 ]
2919 CXCL1; C-X-C motif chemokine ligand 1 [KO:K05505 ]
2920 CXCL2; C-X-C motif chemokine ligand 2 [KO:K05505 ]
2921 CXCL3; C-X-C motif chemokine ligand 3 [KO:K05505 ]
355 FAS; Fas cell surface death receptor [KO:K04390 ]
8772 FADD; Fas associated via death domain [KO:K02373 ]
7132 TNFRSF1A; TNF receptor superfamily member 1A [KO:K03158 ]
8717 TRADD; TNFRSF1A associated via death domain [KO:K03171 ]
257397 TAB3; TGF-beta activated kinase 1 (MAP3K7) binding protein 3 [KO:K12793 ]
6720 SREBF1; sterol regulatory element binding transcription factor 1 [KO:K07197 ]
6434 TRA2B; transformer 2 beta homolog [KO:K12897 ]
9370 ADIPOQ; adiponectin, C1Q and collagen domain containing [KO:K07296 ]
5564 PRKAB1; protein kinase AMP-activated non-catalytic subunit beta 1 [KO:K07199 ]
5565 PRKAB2; protein kinase AMP-activated non-catalytic subunit beta 2 [KO:K07199 ]
5571 PRKAG1; protein kinase AMP-activated non-catalytic subunit gamma 1 [KO:K07200 ]
53632 PRKAG3; protein kinase AMP-activated non-catalytic subunit gamma 3 [KO:K07200 ]
51422 PRKAG2; protein kinase AMP-activated non-catalytic subunit gamma 2 [KO:K07200 ]
5465 PPARA; peroxisome proliferator activated receptor alpha [KO:K07294 ]
2168 FABP1; fatty acid binding protein 1 [KO:K08750 ]
124 ADH1A; alcohol dehydrogenase 1A (class I), alpha polypeptide [KO:K13951 ] [EC:1.1.1.1 ]
125 ADH1B; alcohol dehydrogenase 1B (class I), beta polypeptide [KO:K13951 ] [EC:1.1.1.1 ]
126 ADH1C; alcohol dehydrogenase 1C (class I), gamma polypeptide [KO:K13951 ] [EC:1.1.1.1 ]
131 ADH7; alcohol dehydrogenase 7 (class IV), mu or sigma polypeptide [KO:K13951 ] [EC:1.1.1.1 ]
127 ADH4; alcohol dehydrogenase 4 (class II), pi polypeptide [KO:K13980 ] [EC:1.1.1.1 ]
1571 CYP2E1; cytochrome P450 family 2 subfamily E member 1 [KO:K07415 ] [EC:1.14.14.-]
83439 TCF7L1; transcription factor 7 like 1 [KO:K04490 ]
6934 TCF7L2; transcription factor 7 like 2 [KO:K04491 ]
51176 LEF1; lymphoid enhancer binding factor 1 [KO:K04492 ]
Compound
C22381 Reactive oxygen species
Reference
Authors
Louvet A, Mathurin P
Title
Alcoholic liver disease: mechanisms of injury and targeted treatment.
Journal
Reference
Authors
Gao B, Bataller R
Title
Alcoholic liver disease: pathogenesis and new therapeutic targets.
Journal
Reference
Authors
Magdaleno F, Blajszczak CC, Nieto N
Title
Key Events Participating in the Pathogenesis of Alcoholic Liver Disease.
Journal
Reference
Authors
Lucey MR, Mathurin P, Morgan TR
Title
Alcoholic hepatitis.
Journal
Reference
Authors
Nagy LE, Ding WX, Cresci G, Saikia P, Shah VH
Title
Linking Pathogenic Mechanisms of Alcoholic Liver Disease With Clinical Phenotypes.
Journal
Reference
Authors
Fujii H, Kawada N
Title
Fibrogenesis in alcoholic liver disease.
Journal
Reference
Authors
Kim MS, Ong M, Qu X
Title
Optimal management for alcoholic liver disease: Conventional medications, natural therapy or combination?
Journal
Reference
Authors
You M, Crabb DW
Title
Recent advances in alcoholic liver disease II. Minireview: molecular mechanisms of alcoholic fatty liver.
Journal
Reference
Authors
Nagy LE
Title
The Role of Innate Immunity in Alcoholic Liver Disease.
Journal
Alcohol Res 37:237-50 (2015)
Reference
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
Reference
Authors
Wang HJ, Gao B, Zakhari S, Nagy LE
Title
Inflammation in alcoholic liver disease.
Journal
Reference
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
Reference
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
Reference
Authors
Szabo G, Bala S
Title
Alcoholic liver disease and the gut-liver axis.
Journal
Reference
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
Reference
Authors
Roh YS, Seki E
Title
Toll-like receptors in alcoholic liver disease, non-alcoholic steatohepatitis and carcinogenesis.
Journal
Reference
Authors
Rogers CQ, Ajmo JM, You M
Title
Adiponectin and alcoholic fatty liver disease.
Journal
Reference
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
Reference
Authors
You M, Jogasuria A, Taylor C, Wu J
Title
Sirtuin 1 signaling and alcoholic fatty liver disease.
Journal
Reference
Authors
Ren R, Wang Z, Wu M, Wang H
Title
Emerging Roles of SIRT1 in Alcoholic Liver Disease.
Journal
Reference
Authors
Purohit V, Gao B, Song BJ
Title
Molecular mechanisms of alcoholic fatty liver.
Journal
Reference
Authors
Hyun J, Han J, Lee C, Yoon M, Jung Y
Title
Pathophysiological Aspects of Alcohol Metabolism in the Liver.
Journal
Reference
Authors
Combs TP, Marliss EB
Title
Adiponectin signaling in the liver.
Journal
Reference
Authors
Ceni E, Mello T, Galli A
Title
Pathogenesis of alcoholic liver disease: role of oxidative metabolism.
Journal
Reference
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
Reference
Authors
Ohashi K, Pimienta M, Seki E
Title
Alcoholic liver disease: A current molecular and clinical perspective.
Journal
Reference
Authors
You M, Arteel GE
Title
Effect of ethanol on lipid metabolism.
Journal
Reference
Authors
Bi L, Jiang Z, Zhou J
Title
The role of lipin-1 in the pathogenesis of alcoholic fatty liver.
Journal
Reference
Authors
Ali H, Assiri MA, Shearn CT, Fritz KS
Title
Lipid peroxidation derived reactive aldehydes in alcoholic liver disease.
Journal
Reference
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
Reference
Authors
Stickel F, Hampe J
Title
Genetic determinants of alcoholic liver disease.
Journal
Reference
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
Related pathway
hsa01040 Biosynthesis of unsaturated fatty acids
hsa04610 Complement and coagulation cascades
hsa04620 Toll-like receptor signaling pathway
hsa04920 Adipocytokine signaling pathway
KO pathway
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