Entry Name Non-alcoholic fatty liver disease
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 ko04932 Non-alcoholic fatty liver disease
Disease H01333 Non-alcoholic fatty liver disease
Orthology K00234 SDHA, SDH1; succinate dehydrogenase (ubiquinone) flavoprotein subunit [EC:1.3.5.1 ]
K00235 SDHB, SDH2; succinate dehydrogenase (ubiquinone) iron-sulfur subunit [EC:1.3.5.1 ]
K00236 SDHC, SDH3; succinate dehydrogenase (ubiquinone) cytochrome b560 subunit
K00237 SDHD, SDH4; succinate dehydrogenase (ubiquinone) membrane anchor subunit
K00411 UQCRFS1, RIP1, petA; ubiquinol-cytochrome c reductase iron-sulfur subunit [EC:7.1.1.8 ]
K00412 CYTB, petB; ubiquinol-cytochrome c reductase cytochrome b subunit
K00413 CYC1, CYT1, petC; ubiquinol-cytochrome c reductase cytochrome c1 subunit
K00414 QCR1, UQCRC1; ubiquinol-cytochrome c reductase core subunit 1
K00415 QCR2, UQCRC2; ubiquinol-cytochrome c reductase core subunit 2
K00416 QCR6, UQCRH; ubiquinol-cytochrome c reductase subunit 6
K00417 QCR7, UQCRB; ubiquinol-cytochrome c reductase subunit 7
K00418 QCR8, UQCRQ; ubiquinol-cytochrome c reductase subunit 8
K00419 QCR9, UCRC; ubiquinol-cytochrome c reductase subunit 9
K00420 QCR10, UQCR; ubiquinol-cytochrome c reductase subunit 10
K00922 PIK3CA_B_D; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153 ]
K02159 BAX; apoptosis regulator BAX
K02261 COX2; cytochrome c oxidase subunit 2
K02262 COX3; cytochrome c oxidase subunit 3
K02263 COX4; cytochrome c oxidase subunit 4
K02264 COX5A; cytochrome c oxidase subunit 5a
K02265 COX5B; cytochrome c oxidase subunit 5b
K02266 COX6A; cytochrome c oxidase subunit 6a
K02267 COX6B; cytochrome c oxidase subunit 6b
K02268 COX6C; cytochrome c oxidase subunit 6c
K02270 COX7A; cytochrome c oxidase subunit 7a
K02271 COX7B; cytochrome c oxidase subunit 7b
K02272 COX7C; cytochrome c oxidase subunit 7c
K02273 COX8; cytochrome c oxidase subunit 8
K02580 NFKB1; nuclear factor NF-kappa-B p105 subunit
K02649 PIK3R1_2_3; phosphoinositide-3-kinase regulatory subunit alpha/beta/delta
K03156 TNF, TNFA; tumor necrosis factor superfamily, member 2
K03158 TNFRSF1A, TNFR1, CD120a; tumor necrosis factor receptor superfamily member 1A
K03237 EIF2S1; translation initiation factor 2 subunit 1
K03934 NDUFS1; NADH dehydrogenase (ubiquinone) Fe-S protein 1 [EC:7.1.1.2 ]
K03935 NDUFS2; NADH dehydrogenase (ubiquinone) Fe-S protein 2 [EC:7.1.1.2 ]
K03936 NDUFS3; NADH dehydrogenase (ubiquinone) Fe-S protein 3 [EC:7.1.1.2 ]
K03937 NDUFS4; NADH dehydrogenase (ubiquinone) Fe-S protein 4
K03938 NDUFS5; NADH dehydrogenase (ubiquinone) Fe-S protein 5
K03939 NDUFS6; NADH dehydrogenase (ubiquinone) Fe-S protein 6
K03940 NDUFS7; NADH dehydrogenase (ubiquinone) Fe-S protein 7 [EC:7.1.1.2 ]
K03941 NDUFS8; NADH dehydrogenase (ubiquinone) Fe-S protein 8 [EC:7.1.1.2 ]
K03942 NDUFV1; NADH dehydrogenase (ubiquinone) flavoprotein 1 [EC:7.1.1.2 ]
K03943 NDUFV2; NADH dehydrogenase (ubiquinone) flavoprotein 2 [EC:7.1.1.2 ]
K03944 NDUFV3; NADH dehydrogenase (ubiquinone) flavoprotein 3
K03945 NDUFA1; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 1
K03946 NDUFA2; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 2
K03947 NDUFA3; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 3
K03948 NDUFA4; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 4
K03949 NDUFA5; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 5
K03950 NDUFA6; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 6
K03951 NDUFA7; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 7
K03952 NDUFA8; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 8
K03953 NDUFA9; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 9
K03954 NDUFA10; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 10
K03955 NDUFAB1; NADH dehydrogenase (ubiquinone) 1 alpha/beta subcomplex 1, acyl-carrier protein
K03956 NDUFA11; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 11
K03957 NDUFB1; NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 1
K03958 NDUFB2; NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 2
K03959 NDUFB3; NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 3
K03960 NDUFB4; NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 4
K03961 NDUFB5; NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 5
K03962 NDUFB6; NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 6
K03963 NDUFB7; NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 7
K03964 NDUFB8; NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 8
K03965 NDUFB9; NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 9
K03966 NDUFB10; NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 10
K03967 NDUFC1; NADH dehydrogenase (ubiquinone) 1 subunit C1
K03968 NDUFC2; NADH dehydrogenase (ubiquinone) 1 subunit C2
K04374 ATF4, CREB2; cyclic AMP-dependent transcription factor ATF-4
K04379 FOS; proto-oncogene protein c-fos
K04383 IL1A; interleukin 1 alpha
K04389 TNFSF6, FASL, CD178; tumor necrosis factor ligand superfamily member 6
K04390 TNFRSF6, FAS, CD95; tumor necrosis factor receptor superfamily member 6
K04392 RAC1; Ras-related C3 botulinum toxin substrate 1
K04393 CDC42; cell division control protein 42
K04419 MAP3K11, MLK3; mitogen-activated protein kinase kinase kinase 11 [EC:2.7.11.25 ]
K04426 MAP3K5, ASK1; mitogen-activated protein kinase kinase kinase 5 [EC:2.7.11.25 ]
K04440 JNK; mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:2.7.11.24 ]
K04448 JUN; transcription factor AP-1
K04452 DDIT3, GADD153; DNA damage-inducible transcript 3
K04519 IL1B; interleukin 1 beta
K04696 SOCS3, CIS3; suppressor of cytokine signaling 3
K04726 BID; BH3 interacting domain death agonist
K04735 RELA; transcription factor p65
K05055 IL6R, CD126; interleukin 6 receptor
K05062 LEPR, CD295; leptin receptor
K07187 IRS2; insulin receptor substrate 2
K07197 SREBP1, SREBF1; sterol regulatory element-binding transcription factor 1
K07198 PRKAA, AMPK; 5'-AMP-activated protein kinase, catalytic alpha subunit [EC:2.7.11.31 ]
K07199 PRKAB; 5'-AMP-activated protein kinase, regulatory beta subunit
K07200 PRKAG; 5'-AMP-activated protein kinase, regulatory gamma subunit
K07209 IKBKB, IKKB; inhibitor of nuclear factor kappa-B kinase subunit beta [EC:2.7.11.10 ]
K07294 NR1C1, PPARA; peroxisome proliferator-activated receptor alpha
K07296 ADIPOQ, ACDC; adiponectin
K07297 ADIPOR; adiponectin receptor
K07415 CYP2E1; cytochrome P450 family 2 subfamily E1 [EC:1.14.14.-]
K08524 RXRA, NR2B1; retinoid X receptor alpha
K08530 NR1C3, PPARG; peroxisome proliferator-activated receptor gamma
K08536 NR1H3, LXRA; liver X receptor alpha
K08852 ERN1; serine/threonine-protein kinase/endoribonuclease IRE1 [EC:2.7.11.1 3.1.26.-]
K08860 EIF2AK3, PERK; eukaryotic translation initiation factor 2-alpha kinase 3 [EC:2.7.11.1 ]
K09027 XBP1; X box-binding protein 1
K09055 CEBPA; CCAAT/enhancer binding protein (C/EBP), alpha
K09113 MLX; MAX-like protein X
K10030 IL8, CXCL8; interleukin 8
K11351 NDUFB11; NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 11
K11352 NDUFA12; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 12
K11353 NDUFA13; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 13
K13375 TGFB1; transforming growth factor beta-1
K16172 IRS1; insulin receptor substrate 1
K16341 BCL2L11, BIM; Bcl-2-like protein 11
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 ko04141 Protein processing in endoplasmic reticulum
ko04920 Adipocytokine signaling pathway
