Entry
Name
Non-alcoholic fatty liver disease - Mirounga leonina (Southern elephant seal)
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
mlx04932 Non-alcoholic fatty liver disease
Disease
H01333 Non-alcoholic fatty liver disease
Organism
Mirounga leonina (Southern elephant seal) [GN:
mlx ]
Gene
117997916 NDUFA3; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 3 [KO:K03947 ]
117998558 PPARA; peroxisome proliferator-activated receptor alpha isoform X1 [KO:K07294 ]
117998612 NDUFA6; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 6 [KO:K03950 ]
117998657 ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374 ]
117998878 NDUFA12; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 12 [KO:K11352 ]
117999338 RAC1; ras-related C3 botulinum toxin substrate 1 isoform X1 [KO:K04392 ]
117999490 MLXIPL; carbohydrate-responsive element-binding protein isoform X1 [KO:K09113 ]
118000153 SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197 ]
118000245 PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199 ]
118002128 EIF2S1; eukaryotic translation initiation factor 2 subunit 1 [KO:K03237 ]
118002675 NDUFB1; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 1 [KO:K03957 ]
118004424 PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922 ] [EC:2.7.1.153 ]
118005112 NDUFS7; NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial isoform X1 [KO:K03940 ] [EC:7.1.1.2 ]
118005260 NDUFA13; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 13 [KO:K11353 ]
118005676 PPARG; peroxisome proliferator-activated receptor gamma isoform X1 [KO:K08530 ]
118005738 NDUFA11; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 11 [KO:K03956 ]
118005924 NDUFB7; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 7 [KO:K03963 ]
118005969 NDUFA7; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 7 [KO:K03951 ]
118006042 PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649 ]
118006183 NDUFS6; NADH dehydrogenase [ubiquinone] iron-sulfur protein 6, mitochondrial [KO:K03939 ]
118006277 SDHA; succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial isoform X1 [KO:K00234 ] [EC:1.3.5.1 ]
118006556 PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922 ] [EC:2.7.1.153 ]
118006688 NDUFB5; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 5, mitochondrial [KO:K03961 ]
118007053 NDUFB4; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 4 [KO:K03960 ]
118008679 NDUFA4L2; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 4-like 2 [KO:K03948 ]
118008887 PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200 ]
118009645 NDUFB11; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 11, mitochondrial [KO:K11351 ]
118011878 NDUFA10; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10, mitochondrial isoform X1 [KO:K03954 ]
118012033 PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X1 [KO:K07200 ]
118012157 NDUFB3; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 3 [KO:K03959 ]
118012420 NDUFA1; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1 [KO:K03945 ]
118012958 FAS; tumor necrosis factor receptor superfamily member 6 [KO:K04390 ]
118013236 SDHD; succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial isoform X1 [KO:K00237 ]
118014015 NDUFS2; NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, mitochondrial isoform X1 [KO:K03935 ] [EC:7.1.1.2 ]
118014021 SDHC; succinate dehydrogenase cytochrome b560 subunit, mitochondrial [KO:K00236 ]
118014469 FASLG; LOW QUALITY PROTEIN: tumor necrosis factor ligand superfamily member 6 [KO:K04389 ]
118015199 NDUFB9; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 9 [KO:K03965 ]
118015844 NDUFS3; NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial [KO:K03936 ] [EC:7.1.1.2 ]
118016147 NDUFS8; NADH dehydrogenase [ubiquinone] iron-sulfur protein 8, mitochondrial isoform X1 [KO:K03941 ] [EC:7.1.1.2 ]
118016727 NDUFA2; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 2 [KO:K03946 ]
118016863 PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649 ]
118017734 NDUFA8; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 8 isoform X1 [KO:K03952 ]
118018036 NDUFB6; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 6 isoform X1 [KO:K03962 ]
118018532 PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199 ]
118019468 PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649 ]
118019589 NDUFS5; NADH dehydrogenase [ubiquinone] iron-sulfur protein 5 [KO:K03938 ]
118019913 CDC42; cell division control protein 42 homolog isoform X1 [KO:K04393 ]
118019953 SDHB; succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial [KO:K00235 ] [EC:1.3.5.1 ]
118020028 PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922 ] [EC:2.7.1.153 ]
118021036 NDUFA5; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 5 isoform X1 [KO:K03949 ]
118021161 NDUFB2; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 2, mitochondrial [KO:K03958 ]
118021712 NDUFB10; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 10 [KO:K03966 ]
118022312 NDUFC1; NADH dehydrogenase [ubiquinone] 1 subunit C1, mitochondrial [KO:K03967 ]
118022632 TGFB1; transforming growth factor beta-1 proprotein isoform X1 [KO:K13375 ]
118024372 ERN1; serine/threonine-protein kinase/endoribonuclease IRE1 isoform X1 [KO:K08852 ] [EC:2.7.11.1 3.1.26.-]
118025000 NDUFB8; NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 8, mitochondrial isoform X1 [KO:K03964 ]
118025746 TNFRSF1A; tumor necrosis factor receptor superfamily member 1A isoform X1 [KO:K03158 ]
118025758 NDUFA9; NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9, mitochondrial [KO:K03953 ]
118026822 PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200 ]
118026972 NDUFV3; NADH dehydrogenase [ubiquinone] flavoprotein 3, mitochondrial isoform X1 [KO:K03944 ]
118027047 NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580 ]
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
mlx04141 Protein processing in endoplasmic reticulum
mlx04920 Adipocytokine signaling pathway
KO pathway