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
Disease
H02516 Alcoholic liver disease
Drug
Organism
Homo sapiens (human) [GN:
hsa ]
Gene
10454 TAB1; TGF-beta-activated kinase 1 and MAP3K7-binding protein 1 isoform alpha [KO:K04403 ]
10645 CAMKK2; calcium/calmodulin-dependent protein kinase kinase 2 isoform 1 [KO:K07359 ] [EC:2.7.11.17 ]
10891 PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform 2 [KO:K07202 ]
110384692 C4A_2; complement C4A (Rodgers blood group)-like preproprotein [KO:K03989 ]
114609 TIRAP; toll/interleukin-1 receptor domain-containing adapter protein isoform a [KO:K05403 ]
1147 CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform 1 [KO:K04467 ] [EC:2.7.11.10 ]
125 ADH1B; all-trans-retinol dehydrogenase [NAD(+)] ADH1B isoform 1 [KO:K13951 ] [EC:1.1.1.1 ]
127 ADH4; all-trans-retinol dehydrogenase [NAD(+)] ADH4 isoform 2 [KO:K13980 ] [EC:1.1.1.1 ]
131 ADH7; all-trans-retinol dehydrogenase [NAD(+)] ADH7 isoform 2 [KO:K13951 ] [EC:1.1.1.1 ]
1374 CPT1A; carnitine O-palmitoyltransferase 1, liver isoform isoform 1 [KO:K08765 ] [EC:2.3.1.21 ]
1375 CPT1B; carnitine O-palmitoyltransferase 1, muscle isoform isoform a [KO:K19523 ] [EC:2.3.1.21 ]
148022 TICAM1; TIR domain-containing adapter molecule 1 isoform 1 [KO:K05842 ]
1571 CYP2E1; cytochrome P450 2E1 [KO:K07415 ] [EC:1.14.14.-]
208 AKT2; RAC-beta serine/threonine-protein kinase isoform 1 [KO:K04456 ] [EC:2.7.11.1 ]
2168 FABP1; fatty acid-binding protein, liver [KO:K08750 ]
217 ALDH2; aldehyde dehydrogenase, mitochondrial isoform 1 precursor [KO:K00128 ] [EC:1.2.1.3 ]
219 ALDH1B1; aldehyde dehydrogenase X, mitochondrial precursor [KO:K00128 ] [EC:1.2.1.3 ]
224 ALDH3A2; aldehyde dehydrogenase family 3 member A2 isoform 2 [KO:K00128 ] [EC:1.2.1.3 ]
2309 FOXO3; forkhead box protein O3 isoform 1 [KO:K09408 ]
23118 TAB2; TGF-beta-activated kinase 1 and MAP3K7-binding protein 2 isoform a [KO:K04404 ]
23643 LY96; lymphocyte antigen 96 isoform 1 precursor [KO:K05400 ]
23765 IL17RA; interleukin-17 receptor A isoform 1 precursor [KO:K05164 ]
257397 TAB3; TGF-beta-activated kinase 1 and MAP3K7-binding protein 3 isoform 1 [KO:K12793 ]
2919 CXCL1; growth-regulated alpha protein precursor [KO:K05505 ]
2920 CXCL2; C-X-C motif chemokine 2 precursor [KO:K05505 ]
2921 CXCL3; C-X-C motif chemokine 3 precursor [KO:K05505 ]
29896 TRA2A; transformer-2 protein homolog alpha isoform 1 [KO:K12897 ]
34 ACADM; medium-chain specific acyl-CoA dehydrogenase, mitochondrial isoform a precursor [KO:K00249 ] [EC:1.3.8.7 ]
3439 IFNA1; interferon alpha-1 precursor [KO:K05414 ]
3440 IFNA2; interferon alpha-2 precursor [KO:K05414 ]
3441 IFNA4; interferon alpha-4 precursor [KO:K05414 ]
3442 IFNA5; interferon alpha-5 precursor [KO:K05414 ]
3443 IFNA6; interferon alpha-6 precursor [KO:K05414 ]
3444 IFNA7; interferon alpha-7 precursor [KO:K05414 ]
3445 IFNA8; interferon alpha-8 precursor [KO:K05414 ]
3446 IFNA10; interferon alpha-10 precursor [KO:K05414 ]
3447 IFNA13; interferon alpha-13 precursor [KO:K05414 ]
3448 IFNA14; interferon alpha-14 precursor [KO:K05414 ]
3449 IFNA16; interferon alpha-16 precursor [KO:K05414 ]
3451 IFNA17; interferon alpha-17 precursor [KO:K05414 ]
3452 IFNA21; interferon alpha-21 precursor [KO:K05414 ]
355 FAS; tumor necrosis factor receptor superfamily member 6 isoform 1 precursor [KO:K04390 ]
3551 IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform 1 [KO:K07209 ] [EC:2.7.11.10 ]
3553 IL1B; interleukin-1 beta proprotein [KO:K04519 ]
356 FASLG; tumor necrosis factor ligand superfamily member 6 isoform 1 [KO:K04389 ]
3569 IL6; interleukin-6 isoform 1 precursor [KO:K05405 ]
3576 CXCL8; interleukin-8 isoform 1 precursor [KO:K10030 ]
3592 IL12A; interleukin-12 subunit alpha isoform 4 precursor [KO:K05406 ]
3593 IL12B; interleukin-12 subunit beta precursor [KO:K05425 ]
3654 IRAK1; interleukin-1 receptor-associated kinase 1 isoform 1 [KO:K04730 ] [EC:2.7.11.1 ]
3661 IRF3; interferon regulatory factor 3 isoform 1 [KO:K05411 ]
37 ACADVL; very long-chain specific acyl-CoA dehydrogenase, mitochondrial isoform 1 precursor [KO:K09479 ] [EC:1.3.8.9 ]
3929 LBP; lipopolysaccharide-binding protein precursor [KO:K05399 ]
4217 MAP3K5; mitogen-activated protein kinase kinase kinase 5 isoform 2 [KO:K04426 ] [EC:2.7.11.25 ]
4615 MYD88; myeloid differentiation primary response protein MyD88 isoform 2 [KO:K04729 ]
4790 NFKB1; nuclear factor NF-kappa-B p105 subunit isoform 2 proprotein [KO:K02580 ]
4792 NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734 ]
50507 NOX4; NADPH oxidase 4 isoform a [KO:K21423 ] [EC:1.6.3.-]
51 ACOX1; peroxisomal acyl-coenzyme A oxidase 1 isoform b [KO:K00232 ] [EC:1.3.3.6 ]
51094 ADIPOR1; adiponectin receptor protein 1 [KO:K07297 ]
51176 LEF1; lymphoid enhancer-binding factor 1 isoform 1 [KO:K04492 ]
51422 PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform a [KO:K07200 ]
53632 PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200 ]
5465 PPARA; peroxisome proliferator-activated receptor alpha isoform 1 [KO:K07294 ]
5562 PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform 1 [KO:K07198 ] [EC:2.7.11.31 ]
5563 PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198 ] [EC:2.7.11.31 ]
5564 PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199 ]
5565 PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199 ]
5571 PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform 1 [KO:K07200 ]
5606 MAP2K3; dual specificity mitogen-activated protein kinase kinase 3 isoform B [KO:K04432 ] [EC:2.7.12.2 ]
5608 MAP2K6; dual specificity mitogen-activated protein kinase kinase 6 isoform 1 [KO:K04433 ] [EC:2.7.12.2 ]
5609 MAP2K7; dual specificity mitogen-activated protein kinase kinase 7 isoform 3 [KO:K04431 ] [EC:2.7.12.2 ]
595 CCND1; G1/S-specific cyclin-D1 [KO:K04503 ]
5970 RELA; transcription factor p65 isoform 1 [KO:K04735 ]
6416 MAP2K4; dual specificity mitogen-activated protein kinase kinase 4 isoform 1 [KO:K04430 ] [EC:2.7.12.2 ]
6434 TRA2B; transformer-2 protein homolog beta isoform 1 [KO:K12897 ]
6720 SREBF1; sterol regulatory element-binding protein 1 isoform 2 [KO:K07197 ]
6885 MAP3K7; mitogen-activated protein kinase kinase kinase 7 isoform B [KO:K04427 ] [EC:2.7.11.25 ]
6932 TCF7; transcription factor 7 isoform 1 [KO:K02620 ]
6934 TCF7L2; transcription factor 7-like 2 isoform 17 [KO:K04491 ]
7099 TLR4; toll-like receptor 4 isoform A precursor [KO:K10160 ]
712 C1QA; complement C1q subcomponent subunit A precursor [KO:K03986 ]
713 C1QB; complement C1q subcomponent subunit B isoform 1 precursor [KO:K03987 ]
7132 TNFRSF1A; tumor necrosis factor receptor superfamily member 1A isoform 1 precursor [KO:K03158 ]
714 C1QC; complement C1q subcomponent subunit C isoform 1 precursor [KO:K03988 ]
718 C3; complement C3 preproprotein [KO:K03990 ]
7187 TRAF3; TNF receptor-associated factor 3 isoform 1 [KO:K03174 ]
719 C3AR1; C3a anaphylatoxin chemotactic receptor [KO:K04009 ]
720 C4A; complement C4-A isoform 1 preproprotein [KO:K03989 ]
721 C4B; complement C4-B preproprotein [KO:K03989 ]
727 C5; complement C5 isoform 1 preproprotein [KO:K03994 ]
728 C5AR1; C5a anaphylatoxin chemotactic receptor 1 [KO:K04010 ]
79602 ADIPOR2; adiponectin receptor protein 2 isoform 2 [KO:K07297 ]
83439 TCF7L1; transcription factor 7-like 1 [KO:K04490 ]
84818 IL17RC; interleukin-17 receptor C isoform 2 precursor [KO:K05166 ]
8517 IKBKG; NF-kappa-B essential modulator isoform a [KO:K07210 ]
8717 TRADD; tumor necrosis factor receptor type 1-associated DEATH domain protein [KO:K03171 ]
8737 RIPK1; receptor-interacting serine/threonine-protein kinase 1 isoform 1 [KO:K02861 ] [EC:2.7.11.1 ]
8772 FADD; FAS-associated death domain protein [KO:K02373 ]
929 CD14; monocyte differentiation antigen CD14 precursor [KO:K04391 ]
9641 IKBKE; inhibitor of nuclear factor kappa-B kinase subunit epsilon isoform 1 [KO:K07211 ] [EC:2.7.11.10 ]
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
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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
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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
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Title
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Reference
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Title
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Reference
Authors
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Title
Therapeutic strategies for alcoholic liver disease: Focusing on inflammation and fibrosis (Review).
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Reference
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Roh YS, Seki E
Title
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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
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Title
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Journal
Reference
Authors
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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