Entry
Name
Alcoholic liver disease - Bos taurus (cow)
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
Organism
Bos taurus (cow) [GN:
bta ]
Gene
534961 C1QA; complement C1q subcomponent subunit A precursor [KO:K03986 ]
617435 C1QB; complement C1q subcomponent subunit B precursor [KO:K03987 ]
509968 C1QC; complement C1q subcomponent subunit C precursor [KO:K03988 ]
781663 LOW QUALITY PROTEIN: complement C4-A-like [KO:K03989 ]
540702 C3AR1; C3a anaphylatoxin chemotactic receptor [KO:K04009 ]
512045 C5; complement C5a anaphylatoxin precursor [KO:K03994 ]
493645 C5AR1; C5a anaphylatoxin chemotactic receptor 1 [KO:K04010 ]
512242 LBP; lipopolysaccharide-binding protein precursor [KO:K05399 ]
514978 lipopolysaccharide-binding protein isoform X2 [KO:K05399 ]
281048 CD14; monocyte differentiation antigen CD14 precursor [KO:K04391 ]
531079 TIRAP; toll/interleukin-1 receptor domain-containing adapter protein [KO:K05403 ]
444881 MYD88; myeloid differentiation primary response protein MyD88 [KO:K04729 ]
519958 TAB1; TGF-beta-activated kinase 1 and MAP3K7-binding protein 1 [KO:K04403 ]
540203 TAB2; TGF-beta-activated kinase 1 and MAP3K7-binding protein 2 [KO:K04404 ]
616115 NFKB1; nuclear factor NF-kappa-B p105 subunit [KO:K02580 ]
281856 IL12A; interleukin-12 subunit alpha precursor [KO:K05406 ]
281857 IL12B; interleukin-12 subunit beta precursor [KO:K05425 ]
510427 TICAM1; TIR domain-containing adapter molecule 1 [KO:K05842 ]
617556 LOW QUALITY PROTEIN: interferon alpha-1-like [KO:K05414 ]
525040 IL17RA; interleukin-17 receptor A isoform X1 [KO:K05164 ]
504855 IL17RC; interleukin-17 receptor C precursor [KO:K05166 ]
281212 GRO1; growth-regulated protein homolog alpha precursor [KO:K05505 ]
281214 CXCL2; growth-regulated protein homolog gamma precursor [KO:K05505 ]
613667 CXCL3; chemokine (C-X-C motif) ligand 3 precursor [KO:K05505 ]
407111 FASLG; tumor necrosis factor ligand superfamily member 6 [KO:K04389 ]
282488 FAS; tumor necrosis factor receptor superfamily member 6 precursor [KO:K04390 ]
493720 FADD; FAS-associated death domain protein [KO:K02373 ]
282527 TNFRSF1A; tumor necrosis factor receptor superfamily member 1A precursor [KO:K03158 ]
504707 TRADD; tumor necrosis factor receptor type 1-associated DEATH domain protein [KO:K03171 ]
788288 TAB3; TGF-beta-activated kinase 1 and MAP3K7-binding protein 3 [KO:K12793 ]
539361 SREBF1; sterol regulatory element-binding protein 1 [KO:K07197 ]
534586 TRA2A; transformer-2 protein homolog alpha [KO:K12897 ]
615156 TRA2B; transformer-2 protein homolog beta [KO:K12897 ]
512665 PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199 ]
534107 PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199 ]
282324 PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200 ]
504219 PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200 ]
511961 PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform 1 [KO:K07200 ]
338446 PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha [KO:K07202 ]
281992 PPARA; peroxisome proliferator-activated receptor alpha [KO:K07294 ]
282130 ACADVL; very long-chain specific acyl-CoA dehydrogenase, mitochondrial precursor [KO:K09479 ] [EC:1.3.8.9 ]
505968 ACADM; medium-chain specific acyl-CoA dehydrogenase, mitochondrial precursor [KO:K00249 ] [EC:1.3.8.7 ]
534808 ADH7; LOW QUALITY PROTEIN: all-trans-retinol dehydrogenase [NAD(+)] ADH7 [KO:K13951 ] [EC:1.1.1.1 ]
281618 ALDH1B1; LOW QUALITY PROTEIN: aldehyde dehydrogenase X, mitochondrial [KO:K00128 ] [EC:1.2.1.3 ]
282213 CYP2E1; cytochrome P450 2E1 [KO:K07415 ] [EC:1.14.14.-]
513710 CPT1C; carnitine O-palmitoyltransferase 1, brain isoform isoform X1 [KO:K19524 ] [EC:2.3.1.21 ]
515303 TCF7L1; transcription factor 7-like 1 isoform X1 [KO:K04490 ]
787278 MAP2K7; dual specificity mitogen-activated protein kinase kinase 7 isoform X1 [KO:K04431 ] [EC:2.7.12.2 ]
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
bta01040 Biosynthesis of unsaturated fatty acids
bta04610 Complement and coagulation cascades
bta04620 Toll-like receptor signaling pathway
bta04920 Adipocytokine signaling pathway
KO pathway
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