Entry Name Non-alcoholic fatty liver disease - Chlorocebus sabaeus (green monkey)
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 Chlorocebus sabaeus (green monkey) [GN:
csab ]
Gene 103217881 PRKAG3; protein kinase AMP-activated non-catalytic subunit gamma 3 [KO:K07200 ]
103222594 PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649 ]
103223148 UQCR10; ubiquinol-cytochrome c reductase, complex III subunit X [KO:K00419 ]
103223491 PPARA; peroxisome proliferator activated receptor alpha [KO:K07294 ]
103224726 JUN; Jun proto-oncogene, AP-1 transcription factor subunit [KO:K04448 ]
103224893 UQCRH; ubiquinol-cytochrome c reductase hinge protein [KO:K00416 ]
103224900 PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649 ]
103227261 PRKAG2; protein kinase AMP-activated non-catalytic subunit gamma 2 [KO:K07200 ]
103227597 UQCRC1; ubiquinol-cytochrome c reductase core protein I [KO:K00414 ]
103228027 PPARG; peroxisome proliferator activated receptor gamma [KO:K08530 ]
103229205 EIF2S1; eukaryotic translation initiation factor 2 subunit alpha [KO:K03237 ]
103229352 FOS; Fos proto-oncogene, AP-1 transcription factor subunit [KO:K04379 ]
103229564 UQCR2; ubiquinol-cytochrome c reductase core protein II [KO:K00415 ]
103232235 COX7B; cytochrome c oxidase subunit 7B, mitochondrial [KO:K02271 ]
103234391 PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649 ]
103238254 PRKAG1; protein kinase AMP-activated non-catalytic subunit gamma 1 [KO:K07200 ]
103238561 NDUFA4L2; NDUFA4, mitochondrial complex associated like 2 [KO:K03948 ]
103239238 PRKAB1; protein kinase AMP-activated non-catalytic subunit beta 1 [KO:K07199 ]
103241875 ADIPOQ; adiponectin, C1Q and collagen domain containing [KO:K07296 ]
103242479 SREBF1; sterol regulatory element binding transcription factor 1 [KO:K07197 ]
103243885 COX7A2; cytochrome c oxidase subunit 7A2, mitochondrial [KO:K02270 ]
103244527 UQCRQ; ubiquinol-cytochrome c reductase complex III subunit VII [KO:K00418 ]
103245320 COX5A; cytochrome c oxidase subunit 5A, mitochondrial [KO:K02264 ]
103245979 CYP2E1; cytochrome P450 family 2 subfamily E member 1 [KO:K07415 ] [EC:1.14.14.-]
103246147 COX7B2; cytochrome c oxidase subunit 7B2, mitochondrial [KO:K02271 ]
103246815 RAC1; ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) [KO:K04392 ]
103247234 PRKAB2; protein kinase AMP-activated non-catalytic subunit beta 2 [KO:K07199 ]
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 csab04141 Protein processing in endoplasmic reticulum
KO pathway
