Entry Name Non-alcoholic fatty liver disease - Budorcas taxicolor (takin)
Description Non-alcoholic fatty liver disease (NAFLD) represents a spectrum ranging from simple steatosis to more severe steatohepatitis with hepatic inflammation and fibrosis, known as nonalcoholic steatohepatitis (NASH). NASH may further lead to cirrhosis and hepatocellular carcinoma (HCC). This map shows a stage-dependent progression of NAFLD. In the first stage of NAFLD, excess lipid accumulation has been demonstrated. The main cause is the induction of insulin resistance, which leads to a defect in insulin suppression of free fatty acids (FAAs) disposal. In addition, two transcription factors, SREBP-1c and PPAR-alpha, activate key enzymes of lipogenesis and increase the synthesis of FAAs in liver. In the second stage, as a consequence of the progression to NASH, the production of reactive oxygen species (ROS) is enhanced due to oxidation stress through mitochondrial beta-oxidation of fatty acids and endoplamic reticulum (ER) stress, leading to lipid peroxidation. The lipid peroxidation can further cause the production of cytokines (Fas ligand, TNF-alpha, IL-8 and TGF), promoting cell death, inflammation and fibrosis. The activation of JNK, which is induced by ER stress, TNF-alpha and FAAs, is also associated with NAFLD progression. Increased JNK promotes cytokine production and initiation of HCC.
Class Human Diseases; Endocrine and metabolic diseaseBRITE hierarchy
Pathway map Disease H01333 Non-alcoholic fatty liver disease
Organism Budorcas taxicolor (takin) [GN:
btax ]
Gene 128043200 NDUFB10; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 10 [KO:K03966 ]
128043818 PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X1 [KO:K07200 ]
128044474 PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649 ]
128044487 NDUFS2; NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, mitochondrial [KO:K03935 ] [EC:7.1.1.2 ]
128044593 SDHC; succinate dehydrogenase cytochrome b560 subunit, mitochondrial isoform X1 [KO:K00236 ]
128044635 NDUFA10; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10, mitochondrial [KO:K03954 ]
128045108 PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199 ]
128045118 NDUFV3; NADH dehydrogenase [ubiquinone] flavoprotein 3, mitochondrial isoform X1 [KO:K03944 ]
128045154 NDUFS5; NADH dehydrogenase [ubiquinone] iron-sulfur protein 5 [KO:K03938 ]
128045803 PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922 ] [EC:2.7.1.153 ]
128046252 PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 [KO:K07200 ]
128046403 NDUFA5; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 5 [KO:K03949 ]
128046653 NDUFB5; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 5, mitochondrial [KO:K03961 ]
128046972 NDUFB2; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 2, mitochondrial [KO:K03958 ]
128047601 PPARA; peroxisome proliferator-activated receptor alpha [KO:K07294 ]
128047668 TNFRSF1A; tumor necrosis factor receptor superfamily member 1A isoform X1 [KO:K03158 ]
128047836 NDUFA9; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9, mitochondrial [KO:K03953 ]
128047885 ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374 ]
128048376 NDUFA12; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 12 [KO:K11352 ]
128048517 NDUFA6; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 6 [KO:K03950 ]
128048621 NDUFA4L2; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 4-like 2 [KO:K03948 ]
128048702 PPARG; peroxisome proliferator-activated receptor gamma isoform X1 [KO:K08530 ]
128048815 PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200 ]
128049417 NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580 ]
128050540 PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649 ]
128050721 NDUFA2; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 2 [KO:K03946 ]
128050799 NDUFS7; NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial [KO:K03940 ] [EC:7.1.1.2 ]
128051202 NDUFB7; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 7 [KO:K03963 ]
128051330 NDUFA7; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 7 [KO:K03951 ]
128051389 NDUFA13; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 13 [KO:K11353 ]
128051437 NDUFA11; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 11 [KO:K03956 ]
128052403 NDUFB6; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 6 [KO:K03962 ]
128053787 NDUFB4; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 4 [KO:K03960 ]
128054117 EIF2S1; eukaryotic translation initiation factor 2 subunit 1 [KO:K03237 ]
128056168 NDUFA8; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 8 [KO:K03952 ]
128057660 IRS2; LOW QUALITY PROTEIN: insulin receptor substrate 2 [KO:K07187 ]
128059268 NDUFB9; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 9 [KO:K03965 ]
128060079 SDHD; succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial [KO:K00237 ]
128060120 NDUFS3; NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial [KO:K03936 ] [EC:7.1.1.2 ]
128061812 FASLG; tumor necrosis factor ligand superfamily member 6 [KO:K04389 ]
128061813 PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922 ] [EC:2.7.1.153 ]
128061956 MLXIPL; carbohydrate-responsive element-binding protein [KO:K09113 ]
128062051 PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199 ]
128062454 NDUFC1; NADH dehydrogenase [ubiquinone] 1 subunit C1, mitochondrial [KO:K03967 ]
128063056 NDUFA3; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 3 [KO:K03947 ]
128066111 NDUFS4; NADH dehydrogenase [ubiquinone] iron-sulfur protein 4, mitochondrial [KO:K03937 ]
128066127 NDUFS6; NADH dehydrogenase [ubiquinone] iron-sulfur protein 6, mitochondrial [KO:K03939 ]
128066232 SDHA; succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial [KO:K00234 ] [EC:1.3.5.1 ]
128066235 PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649 ]
128066401 CDC42; cell division control protein 42 homolog isoform X1 [KO:K04393 ]
128066874 NDUFB1; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 1 [KO:K03957 ]
128067819 NDUFB8; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 8, mitochondrial [KO:K03964 ]
128067868 NDUFB3; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 3 isoform X1 [KO:K03959 ]
128067871 FAS; tumor necrosis factor receptor superfamily member 6 [KO:K04390 ]
128068699 PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922 ] [EC:2.7.1.153 ]
128068819 NDUFS8; NADH dehydrogenase [ubiquinone] iron-sulfur protein 8, mitochondrial isoform X1 [KO:K03941 ] [EC:7.1.1.2 ]
128069029 SDHB; succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial isoform X1 [KO:K00235 ] [EC:1.3.5.1 ]
128070595 NDUFB11; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 11, mitochondrial [KO:K11351 ]
Compound Reference Authors Naik A, Kosir R, Rozman D
Title Genomic aspects of NAFLD pathogenesis.
Journal Reference Authors Malaguarnera M, Di Rosa M, Nicoletti F, Malaguarnera L
Title Molecular mechanisms involved in NAFLD progression.
Journal Reference Authors Seki E, Brenner DA, Karin M
Title A liver full of JNK: signaling in regulation of cell function and disease pathogenesis, and clinical approaches.
Journal Reference Authors Tilg H, Moschen AR
Title Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis.
Journal Reference Authors Larter CZ, Farrell GC
Title Insulin resistance, adiponectin, cytokines in NASH: Which is the best target to treat?
Journal Reference Authors Farrell GC, van Rooyen D, Gan L, Chitturi S
Title NASH is an Inflammatory Disorder: Pathogenic, Prognostic and Therapeutic Implications.
Journal Reference Authors Shapiro H, Tehilla M, Attal-Singer J, Bruck R, Luzzatti R, Singer P
Title The therapeutic potential of long-chain omega-3 fatty acids in nonalcoholic fatty liver disease.
Journal Reference Authors Hotamisligil GS
Title Endoplasmic reticulum stress and the inflammatory basis of metabolic disease.
Journal Reference Authors Parekh S, Anania FA
Title Abnormal lipid and glucose metabolism in obesity: implications for nonalcoholic fatty liver disease.
Journal Reference Authors Schattenberg JM, Singh R, Wang Y, Lefkowitch JH, Rigoli RM, Scherer PE, Czaja MJ
Title JNK1 but not JNK2 promotes the development of steatohepatitis in mice.
Journal Reference Authors Leung TM, Nieto N
Title CYP2E1 and oxidant stress in alcoholic and non-alcoholic fatty liver disease.
Journal Reference Authors Zafrani ES
Title Non-alcoholic fatty liver disease: an emerging pathological spectrum.
Journal Reference Authors Feldstein AE, Canbay A, Angulo P, Taniai M, Burgart LJ, Lindor KD, Gores GJ
Title Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis.
Journal Reference Authors Begriche K, Igoudjil A, Pessayre D, Fromenty B
Title Mitochondrial dysfunction in NASH: causes, consequences and possible means to prevent it.
Journal Reference Authors Leonarduzzi G, Scavazza A, Biasi F, Chiarpotto E, Camandola S, Vogel S, Dargel R, Poli G
Title The lipid peroxidation end product 4-hydroxy-2,3-nonenal up-regulates transforming growth factor beta1 expression in the macrophage lineage: a link between oxidative injury and fibrosclerosis.
Journal Reference Authors Malhi H, Kaufman RJ
Title Endoplasmic reticulum stress in liver disease.
Journal Reference Authors Mantena SK, King AL, Andringa KK, Eccleston HB, Bailey SM
Title Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases.
Journal Reference Authors Serviddio G, Sastre J, Bellanti F, Vina J, Vendemiale G, Altomare E
Title Mitochondrial involvement in non-alcoholic steatohepatitis.
Journal Reference Authors Begriche K, Massart J, Robin MA, Bonnet F, Fromenty B
Title Mitochondrial adaptations and dysfunctions in nonalcoholic fatty liver disease.
Journal Related btax04141 Protein processing in endoplasmic reticulum
KO pathway
