Entry Name Non-alcoholic fatty liver disease - Ursus maritimus (polar bear)
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 umr04932 Non-alcoholic fatty liver disease
Disease H01333 Non-alcoholic fatty liver disease
Organism Ursus maritimus (polar bear) [GN:
umr ]
Gene 103656234 TNFRSF1A; tumor necrosis factor receptor superfamily member 1A isoform X1 [KO:K03158 ]
103656470 NDUFA4L2; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 4-like 2 [KO:K03948 ]
103657962 NDUFC1; NADH dehydrogenase [ubiquinone] 1 subunit C1, mitochondrial [KO:K03967 ]
103658535 SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197 ]
103659737 NDUFB3; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 3 [KO:K03959 ]
103660109 NDUFA12; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 12 [KO:K11352 ]
103660987 PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200 ]
103661621 NDUFB9; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 9 [KO:K03965 ]
103661934 FAS; tumor necrosis factor receptor superfamily member 6 [KO:K04390 ]
103662415 NDUFV2; NADH dehydrogenase [ubiquinone] flavoprotein 2, mitochondrial isoform X1 [KO:K03943 ] [EC:7.1.1.2 ]
103662753 PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200 ]
103662822 NDUFA10; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10, mitochondrial isoform X1 [KO:K03954 ]
103663617 PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X3 [KO:K02649 ]
103663752 NDUFA2; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 2 [KO:K03946 ]
103664628 NDUFS4; NADH dehydrogenase [ubiquinone] iron-sulfur protein 4, mitochondrial [KO:K03937 ]
103666354 NDUFS5; NADH dehydrogenase [ubiquinone] iron-sulfur protein 5 [KO:K03938 ]
103666614 SDHB; succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial [KO:K00235 ] [EC:1.3.5.1 ]
103666874 PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922 ] [EC:2.7.1.153 ]
103667024 NDUFB6; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 6 [KO:K03962 ]
103668115 FASLG; tumor necrosis factor ligand superfamily member 6 [KO:K04389 ]
103668717 IL6R; interleukin-6 receptor subunit alpha isoform X1 [KO:K05055 ]
103668772 NDUFB10; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 10 [KO:K03966 ]
103669030 NDUFB2; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 2, mitochondrial [KO:K03958 ]
103669544 PPARG; peroxisome proliferator-activated receptor gamma isoform X1 [KO:K08530 ]
103669950 NDUFB11; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 11, mitochondrial isoform X2 [KO:K11351 ]
103670223 MLXIPL; carbohydrate-responsive element-binding protein isoform X1 [KO:K09113 ]
103670360 NDUFA8; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 8 [KO:K03952 ]
103670766 PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649 ]
103671936 EIF2S1; eukaryotic translation initiation factor 2 subunit 1 [KO:K03237 ]
103672010 SDHC; succinate dehydrogenase cytochrome b560 subunit, mitochondrial [KO:K00236 ]
103672016 NDUFS2; NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, mitochondrial isoform X1 [KO:K03935 ] [EC:7.1.1.2 ]
103672304 NDUFS3; NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial [KO:K03936 ] [EC:7.1.1.2 ]
103672884 NDUFA3; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 3 [KO:K03947 ]
103673805 NDUFB1; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 1 [KO:K03957 ]
103674025 PPARA; peroxisome proliferator-activated receptor alpha isoform X1 [KO:K07294 ]
103674068 NDUFA6; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 6 [KO:K03950 ]
103674915 NDUFA13; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 13 [KO:K11353 ]
103675162 PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649 ]
103675453 PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200 ]
103675753 NDUFA9; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9, mitochondrial isoform X1 [KO:K03953 ]
103676116 NDUFB5; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 5, mitochondrial isoform X2 [KO:K03961 ]
103676125 PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922 ] [EC:2.7.1.153 ]
103676372 ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374 ]
103676612 NDUFA5; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 5 [KO:K03949 ]
103677394 TGFB1; transforming growth factor beta-1 proprotein isoform X1 [KO:K13375 ]
103677527 NDUFB8; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 8, mitochondrial [KO:K03964 ]
103677743 NDUFA1; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1 [KO:K03945 ]
103677947 NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580 ]
103678332 PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 isoform X2 [KO:K07199 ]
103678391 PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X2 [KO:K07199 ]
103678592 PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922 ] [EC:2.7.1.153 ]
103678783 NDUFB4; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 4 [KO:K03960 ]
103679235 NDUFS6; NADH dehydrogenase [ubiquinone] iron-sulfur protein 6, mitochondrial isoform X1 [KO:K03939 ]
103679246 SDHA; succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial isoform X1 [KO:K00234 ] [EC:1.3.5.1 ]
103679622 NDUFS8; NADH dehydrogenase [ubiquinone] iron-sulfur protein 8, mitochondrial isoform X1 [KO:K03941 ] [EC:7.1.1.2 ]
103680708 NDUFV3; NADH dehydrogenase [ubiquinone] flavoprotein 3, mitochondrial isoform X1 [KO:K03944 ]
103681635 NDUFS7; NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial isoform X1 [KO:K03940 ] [EC:7.1.1.2 ]
103681700 NDUFA11; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 11 [KO:K03956 ]
103681725 NDUFA7; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 7 [KO:K03951 ]
103682114 NDUFB7; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 7 [KO:K03963 ]
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 umr04141 Protein processing in endoplasmic reticulum
umr04920 Adipocytokine signaling pathway
KO pathway
