Entry
Name
Non-alcoholic fatty liver disease - Neogale vison (American mink)
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 disease
BRITE hierarchy
Pathway map
nvs04932 Non-alcoholic fatty liver disease
Ortholog table
Organism
Neogale vison (American mink) [GN:
nvs ]
Gene
122918234 IL6R; interleukin-6 receptor subunit alpha isoform X1 [KO:K05055 ]
122892505 TNFRSF1A; tumor necrosis factor receptor superfamily member 1A [KO:K03158 ]
122889330 NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580 ]
122899425 PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922 ] [EC:2.7.1.153 ]
122908712 PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922 ] [EC:2.7.1.153 ]
122908899 PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922 ] [EC:2.7.1.153 ]
122918946 PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649 ]
122899916 PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649 ]
122909588 PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649 ]
122906856 SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197 ]
122895803 MLXIPL; carbohydrate-responsive element-binding protein isoform X1 [KO:K09113 ]
122900404 PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199 ]
122903371 PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199 ]
122905216 PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200 ]
122891254 PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200 ]
122901740 PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200 ]
122892035 PPARA; peroxisome proliferator-activated receptor alpha [KO:K07294 ]
122909195 PPARG; peroxisome proliferator-activated receptor gamma isoform X1 [KO:K08530 ]
122899548 CDC42; cell division control protein 42 homolog isoform X1 [KO:K04393 ]
122895963 RAC1; ras-related C3 botulinum toxin substrate 1 isoform X1 [KO:K04392 ]
122918121 FASLG; tumor necrosis factor ligand superfamily member 6 [KO:K04389 ]
122912064 TGFB1; transforming growth factor beta-1 proprotein isoform X1 [KO:K13375 ]
122893967 EIF2S1; eukaryotic translation initiation factor 2 subunit 1 [KO:K03237 ]
122891883 ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374 ]
122900656 FAS; tumor necrosis factor receptor superfamily member 6 [KO:K04390 ]
122908267 NDUFV3; NADH dehydrogenase [ubiquinone] flavoprotein 3, mitochondrial isoform X1 [KO:K03944 ]
122897149 NDUFA1; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1 [KO:K03945 ]
122915592 NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1-like [KO:K03945 ]
122890557 NDUFA2; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 2 [KO:K03946 ]
122911678 NDUFA3; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 3 [KO:K03947 ]
122891482 NDUFA4L2; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 4-like 2 [KO:K03948 ]
122894691 LOW QUALITY PROTEIN: cytochrome c oxidase subunit NDUFA4-like [KO:K03948 ]
122903641 LOW QUALITY PROTEIN: cytochrome c oxidase subunit NDUFA4-like [KO:K03948 ]
122905031 NDUFA5; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 5 [KO:K03949 ]
122891864 NDUFA6; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 6 [KO:K03950 ]
122909803 NDUFA7; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 7 [KO:K03951 ]
122917290 NDUFA8; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 8 [KO:K03952 ]
122891108 NDUFA9; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9, mitochondrial [KO:K03953 ]
122902465 NDUFA10; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10, mitochondrial [KO:K03954 ]
122909833 NDUFA11; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 11 [KO:K03956 ]
122891747 NDUFA12; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 12 [KO:K11352 ]
122909517 NDUFA13; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 13 [KO:K11353 ]
122894479 NDUFB1; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 1 [KO:K03957 ]
122905137 NDUFB2; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 2, mitochondrial [KO:K03958 ]
122902186 NDUFB3; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 3 [KO:K03959 ]
122908543 NDUFB4; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 4 [KO:K03960 ]
122909800 NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 4-like [KO:K03960 ]
122908719 NDUFB5; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 5, mitochondrial isoform X1 [KO:K03961 ]
122917534 NDUFB6; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 6 [KO:K03962 ]
122909545 NDUFB7; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 7 [KO:K03963 ]
122901022 NDUFB8; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 8, mitochondrial [KO:K03964 ]
122904311 NDUFB9; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 9 [KO:K03965 ]
122896181 NDUFB10; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 10 [KO:K03966 ]
122897625 NDUFB11; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 11, mitochondrial [KO:K11351 ]
122918373 NDUFS2; NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, mitochondrial isoform X1 [KO:K03935 ] [EC:7.1.1.2 ]
122912907 NDUFS3; NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial [KO:K03936 ] [EC:7.1.1.2 ]
122894329 NDUFS4; NADH dehydrogenase [ubiquinone] iron-sulfur protein 4, mitochondrial [KO:K03937 ]
122897039 NADH dehydrogenase [ubiquinone] iron-sulfur protein 5-like [KO:K03938 ]
122906214 NADH dehydrogenase [ubiquinone] iron-sulfur protein 5-like [KO:K03938 ]
122899787 NDUFS5; NADH dehydrogenase [ubiquinone] iron-sulfur protein 5 [KO:K03938 ]
122908823 NADH dehydrogenase [ubiquinone] iron-sulfur protein 5-like [KO:K03938 ]
122896151 NDUFS6; NADH dehydrogenase [ubiquinone] iron-sulfur protein 6, mitochondrial isoform X1 [KO:K03939 ]
122909951 NDUFS7; NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial [KO:K03940 ] [EC:7.1.1.2 ]
122913199 NDUFS8; NADH dehydrogenase [ubiquinone] iron-sulfur protein 8, mitochondrial isoform X1 [KO:K03941 ] [EC:7.1.1.2 ]
122919183 NDUFC1; NADH dehydrogenase [ubiquinone] 1 subunit C1, mitochondrial [KO:K03967 ]
122892467 NADH dehydrogenase [ubiquinone] 1 subunit C1, mitochondrial-like [KO:K03967 ]
122903016 NADH dehydrogenase [ubiquinone] 1 subunit C1, mitochondrial-like [KO:K03967 ]
122896387 SDHA; succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial isoform X1 [KO:K00234 ] [EC:1.3.5.1 ]
122899501 SDHB; succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial [KO:K00235 ] [EC:1.3.5.1 ]
122918379 SDHC; succinate dehydrogenase cytochrome b560 subunit, mitochondrial [KO:K00236 ]
122910054 LOW QUALITY PROTEIN: succinate dehydrogenase cytochrome b560 subunit, mitochondrial-like [KO:K00236 ]
122912281 SDHD; succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial isoform X1 [KO:K00237 ]
122899923 cytochrome b-c1 complex subunit 6, mitochondrial isoform X1 [KO:K00416 ]
122915598 cytochrome c oxidase subunit 4 isoform 2, mitochondrial isoform X1 [KO:K02263 ]
122911162 cytochrome c oxidase subunit 4 isoform 1, mitochondrial [KO:K02263 ]
122912869 LOW QUALITY PROTEIN: cytochrome c oxidase subunit 6B1-like [KO:K02267 ]
122915125 cytochrome c oxidase subunit 7A-related protein, mitochondrial [KO:K02270 ]
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 pathway
nvs04141 Protein processing in endoplasmic reticulum
nvs04920 Adipocytokine signaling pathway
KO pathway
LinkDB
All DBs