Entry Name Alcoholic liver disease
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 diseaseBRITE hierarchy
Pathway map Disease H02516 Alcoholic liver disease
Orthology K00121 frmA, ADH5, adhC; S-(hydroxymethyl)glutathione dehydrogenase / alcohol dehydrogenase [EC:1.1.1.284 1.1.1.1 ]
K00507 SCD, desC; stearoyl-CoA desaturase (Delta-9 desaturase) [EC:1.14.19.1 ]
K02373 FADD; FAS-associated death domain protein
K02580 NFKB1; nuclear factor NF-kappa-B p105 subunit
K02620 TCF7, TCF-1; transcription factor 7
K02861 RIPK1, RIP1; receptor-interacting serine/threonine-protein kinase 1 [EC:2.7.11.1 ]
K03156 TNF, TNFA; tumor necrosis factor superfamily, member 2
K03158 TNFRSF1A, TNFR1, CD120a; tumor necrosis factor receptor superfamily member 1A
K03171 TRADD; tumor necrosis factor receptor type 1-associated DEATH domain protein
K03174 TRAF3; TNF receptor-associated factor 3
K03986 C1QA; complement C1q subcomponent subunit A
K03987 C1QB; complement C1q subcomponent subunit B
K03988 C1QG; complement C1q subcomponent subunit C
K03989 C4; complement component 4
K03990 C3; complement component 3
K03994 C5; complement component 5
K04009 C3AR1; C3a anaphylatoxin chemotactic receptor
K04010 C5AR1, CD88; C5a anaphylatoxin chemotactic receptor 1
K04389 TNFSF6, FASL, CD178; tumor necrosis factor ligand superfamily member 6
K04390 TNFRSF6, FAS, CD95; tumor necrosis factor receptor superfamily member 6
K04391 CD14; monocyte differentiation antigen CD14
K04403 MAP3K7IP1, TAB1; TAK1-binding protein 1
K04404 MAP3K7IP2, TAB2; TAK1-binding protein 2
K04426 MAP3K5, ASK1; mitogen-activated protein kinase kinase kinase 5 [EC:2.7.11.25 ]
K04427 MAP3K7, TAK1; mitogen-activated protein kinase kinase kinase 7 [EC:2.7.11.25 ]
K04430 MAP2K4, MKK4; mitogen-activated protein kinase kinase 4 [EC:2.7.12.2 ]
K04431 MAP2K7, MKK7; mitogen-activated protein kinase kinase 7 [EC:2.7.12.2 ]
K04432 MAP2K3, MKK3; mitogen-activated protein kinase kinase 3 [EC:2.7.12.2 ]
K04433 MAP2K6, MKK6; mitogen-activated protein kinase kinase 6 [EC:2.7.12.2 ]
K04440 JNK; mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:2.7.11.24 ]
K04466 MAP3K14, NIK; mitogen-activated protein kinase kinase kinase 14 [EC:2.7.11.25 ]
K04467 IKBKA, IKKA, CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha [EC:2.7.11.10 ]
K04490 TCF7L1; transcription factor 7-like 1
K04491 TCF7L2; transcription factor 7-like 2
K04492 LEF1; lymphoid enhancer-binding factor 1
K04503 CCND1; G1/S-specific cyclin-D1
K04519 IL1B; interleukin 1 beta
K04729 MYD88; myeloid differentiation primary response protein MyD88
K04730 IRAK1; interleukin-1 receptor-associated kinase 1 [EC:2.7.11.1 ]
K04733 IRAK4; interleukin-1 receptor-associated kinase 4 [EC:2.7.11.1 ]
K04734 NFKBIA; NF-kappa-B inhibitor alpha
K04735 RELA; transcription factor p65
K05164 IL17RA, CD217; interleukin 17 receptor A
K05166 IL17RC, IL17RL; interleukin 17 receptor C
K05399 LBP; lipopolysaccharide-binding protein
K05400 LY96, MD-2; lymphocyte antigen 96
K05403 TIRAP; toll-interleukin 1 receptor (TIR) domain-containing adaptor protein
K05411 IRF3; interferon regulatory factor 3
K05489 IL17A, CTLA8; interleukin 17A
K05505 CXCL1_2_3, GRO; C-X-C motif chemokine 1/2/3
K05842 TRIF; toll-like receptor adapter molecule 1
K07197 SREBP1, SREBF1; sterol regulatory element-binding transcription factor 1
K07198 PRKAA, AMPK; 5'-AMP-activated protein kinase, catalytic alpha subunit [EC:2.7.11.31 ]
K07199 PRKAB; 5'-AMP-activated protein kinase, regulatory beta subunit
K07200 PRKAG; 5'-AMP-activated protein kinase, regulatory gamma subunit
K07201 FOXO1; forkhead box protein O1
K07202 PPARGC1A, PGC1A; alpha peroxisome proliferator-activated receptor gamma coactivator 1-alpha
K07209 IKBKB, IKKB; inhibitor of nuclear factor kappa-B kinase subunit beta [EC:2.7.11.10 ]
K07210 IKBKG, IKKG, NEMO; inhibitor of nuclear factor kappa-B kinase subunit gamma
K07211 IKBKE, IKKE; inhibitor of nuclear factor kappa-B kinase subunit epsilon [EC:2.7.11.10 ]
K07294 NR1C1, PPARA; peroxisome proliferator-activated receptor alpha
K07296 ADIPOQ, ACDC; adiponectin
K07297 ADIPOR; adiponectin receptor
K07359 CAMKK2; calcium/calmodulin-dependent protein kinase kinase 2 [EC:2.7.11.17 ]
K07415 CYP2E1; cytochrome P450 family 2 subfamily E1 [EC:1.14.14.-]
K08750 FABP1, L-FABP; fatty acid-binding protein 1, liver
K08765 CPT1A; carnitine O-palmitoyltransferase 1, liver isoform [EC:2.3.1.21 ]
K09408 FOXO3; forkhead box protein O3
K09479 ACADVL; very long chain acyl-CoA dehydrogenase [EC:1.3.8.9 ]
K10030 IL8, CXCL8; interleukin 8
K10160 TLR4, CD284; toll-like receptor 4
K11411 SIRT1, SIR2L1; NAD-dependent protein deacetylase sirtuin 1 [EC:2.3.1.286 ]
K12793 MAP3K7IP3, TAB3; TAK1-binding protein 3
K12897 TRA2; transformer-2 protein
K19523 CPT1B; carnitine O-palmitoyltransferase 1, muscle isoform [EC:2.3.1.21 ]
K19524 CPT1C; carnitine O-palmitoyltransferase 1, brain isoform [EC:2.3.1.21 ]
K21423 NOX4, RENOX; NADPH oxidase 4 [EC:1.6.3.-]
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 ko00540 Lipopolysaccharide biosynthesis
ko01040 Biosynthesis of unsaturated fatty acids
ko04064 NF-kappa B signaling pathway
ko04610 Complement and coagulation cascades
ko04620 Toll-like receptor signaling pathway
ko04920 Adipocytokine signaling pathway
