Entry Name Non-alcoholic fatty liver disease - Ochotona princeps (American pika)
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 opi04932 Non-alcoholic fatty liver disease
Disease H01333 Non-alcoholic fatty liver disease
Organism Ochotona princeps (American pika) [GN:
opi ]
Gene 101516596 NDUFS2; NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, mitochondrial [KO:K03935 ] [EC:7.1.1.2 ]
101517444 NDUFA10; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10, mitochondrial [KO:K03954 ]
101517745 SDHC; succinate dehydrogenase cytochrome b560 subunit, mitochondrial isoform X1 [KO:K00236 ]
101517919 NDUFB5; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 5, mitochondrial isoform X1 [KO:K03961 ]
101517982 PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649 ]
101518296 SDHD; succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial isoform X1 [KO:K00237 ]
101518340 NDUFB10; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 10 [KO:K03966 ]
101518780 NDUFA12; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 12 [KO:K11352 ]
101519449 PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922 ] [EC:2.7.1.153 ]
101520164 PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199 ]
101520490 NDUFB9; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 9 isoform X1 [KO:K03965 ]
101520662 MLXIPL; carbohydrate-responsive element-binding protein isoform X1 [KO:K09113 ]
101521307 NDUFS4; NADH dehydrogenase [ubiquinone] iron-sulfur protein 4, mitochondrial [KO:K03937 ]
101521494 SDHB; succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial isoform X1 [KO:K00235 ] [EC:1.3.5.1 ]
101521567 ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374 ]
101521864 NDUFA4L2; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 4-like 2 [KO:K03948 ]
101522263 NDUFB3; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 3 [KO:K03959 ]
101522715 EIF2S1; eukaryotic translation initiation factor 2 subunit 1 [KO:K03237 ]
101523318 NDUFA11; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 11 [KO:K03956 ]
101523365 NDUFA2; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 2 [KO:K03946 ]
101523703 NDUFS5; NADH dehydrogenase [ubiquinone] iron-sulfur protein 5 [KO:K03938 ]
101524169 NDUFS3; NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial [KO:K03936 ] [EC:7.1.1.2 ]
101524207 PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199 ]
101524227 NDUFB6; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 6 isoform X1 [KO:K03962 ]
101525197 NDUFA1; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1 [KO:K03945 ]
101525285 NDUFC2; NADH dehydrogenase [ubiquinone] 1 subunit C2 isoform X1 [KO:K03968 ]
101525361 NDUFC1; NADH dehydrogenase [ubiquinone] 1 subunit C1, mitochondrial [KO:K03967 ]
101526129 PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200 ]
101526271 NDUFA13; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 13 [KO:K11353 ]
101526600 NDUFB2; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 2, mitochondrial [KO:K03958 ]
101526820 PPARA; peroxisome proliferator-activated receptor alpha [KO:K07294 ]
101527720 NDUFB11; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 11, mitochondrial isoform X2 [KO:K11351 ]
101528266 FASLG; tumor necrosis factor ligand superfamily member 6 [KO:K04389 ]
101528278 NDUFV1; NADH dehydrogenase [ubiquinone] flavoprotein 1, mitochondrial isoform X1 [KO:K03942 ] [EC:7.1.1.2 ]
101528550 NDUFB1; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 1 [KO:K03957 ]
101528938 FAS; tumor necrosis factor receptor superfamily member 6 [KO:K04390 ]
101529815 NDUFA9; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9, mitochondrial [KO:K03953 ]
101529822 NDUFS8; NADH dehydrogenase [ubiquinone] iron-sulfur protein 8, mitochondrial [KO:K03941 ] [EC:7.1.1.2 ]
101530204 BID; LOW QUALITY PROTEIN: BH3-interacting domain death agonist [KO:K04726 ]
101530247 PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200 ]
101530319 TNFRSF1A; tumor necrosis factor receptor superfamily member 1A [KO:K03158 ]
101530589 NDUFB8; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 8, mitochondrial [KO:K03964 ]
101531611 NFKB1; LOW QUALITY PROTEIN: nuclear factor NF-kappa-B p105 subunit [KO:K02580 ]
101532354 PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649 ]
101532470 CDC42; cell division control protein 42 homolog isoform X1 [KO:K04393 ]
101532825 NDUFB4; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 4 [KO:K03960 ]
101533024 PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922 ] [EC:2.7.1.153 ]
101533139 SDHA; succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial isoform X1 [KO:K00234 ] [EC:1.3.5.1 ]
101533802 PPARG; peroxisome proliferator-activated receptor gamma isoform X1 [KO:K08530 ]
101533851 PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X3 [KO:K00922 ] [EC:2.7.1.153 ]
101534341 NDUFA3; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 3 [KO:K03947 ]
101535143 PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200 ]
101535622 NDUFA6; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 6 isoform X2 [KO:K03950 ]
101535652 NDUFS1; NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial isoform X1 [KO:K03934 ] [EC:7.1.1.2 ]
101535733 NDUFS6; NADH dehydrogenase [ubiquinone] iron-sulfur protein 6, mitochondrial [KO:K03939 ]
101535919 NDUFA5; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 5 isoform X1 [KO:K03949 ]
101536539 NDUFS7; NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial [KO:K03940 ] [EC:7.1.1.2 ]
101536639 SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197 ]
105942376 NDUFA7; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 7 [KO:K03951 ]
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 opi04141 Protein processing in endoplasmic reticulum
opi04920 Adipocytokine signaling pathway
KO pathway
