Roles of ceramides in development of insulin resistance (Homo sapiens)

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Skeletal muscle cell TRAF111, 2, 7, 112272229372774278Insulin promoterROSDownregulationMetaboliteLegendER StressSkeletal muscle cell11Fatty Acid OxidationOxidative stress responseGLUT4 translocationCPT1B10RPS6KB1ACSL1MAPK8TNFRCD36/FATGLUT4ERN1PP1IRS-1pY6pSSphingomyelinPalmitateIRS-2ceramideINSRPP2APKCzetaTNF-alphaAKT1PPI3KPalmitoyl-CoAMAFA4glucoseOleic acidInsulinEIF2AK2OAnSMase2P2PDX14Sphingolipid pathwayAMPKP572PalmitateIRS-1pYpY6IRS-2UpregulationStimulationConversionCatalysisInhibitionUptakenProteinPathway


Description

Ceramides and insulin resistance are connectedd. Ceramides are accumulated in tissues due to an excess of saturated fatty acids. In obese subjects, the amount of ceramides found in skeletal muscles is nearly double that of healthy subjects.

Ceramides are produced mostly by the sphingolipid pathway. Besides the sphingolipid pathway, ceramides are also produced by the hydrolysis of sphingomyelin with the catalysis of nSMase2.

In the cell, ceramides play a role in insulin resistance. Ceramides inhibit the binding of PDX-1 and MAFA transcription factors to insulin promoter. Ceramides cause ER stress, which activates extracellular signal-regulated kinase MAPK8 and EIF2AK2. This leads to the upregulation of serine phosphorylation while downregulating tyrosine phosphorylation of IRS-1. That, in turn, leads to the inhibition of recruitment and activation of PI3K. This leads to a downregulation in AKT1, an enzyme that stimulates the translocation of GLUT4. Ceramides also impair mitochondria functions and inhibit fatty acid oxidation, eventually leading to ROS and inflammation. Ceramides activate protein PP2A, which promotes the dephosphorylation of AKT1. PKCζ is also activated by ceramides to inhibit the activity of AKT1.

Moreover, palmitoyl-CoA downregulates the phosphorylation of AMPK, which leads to the increase of ER stress in the cell and decreases in fatty acid oxidation.

On the other hand, oleic acid inhibits the downregulation of AMPK caused by palmitoyl-CoA. Oleic acid also increases the expression of CPT1B, stimulating the fatty acid oxidation to reduce the inflammation in the cell.

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Bibliography

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  1. Salvadó L, Palomer X, Barroso E, Vázquez-Carrera M; ''Targeting endoplasmic reticulum stress in insulin resistance.''; Trends Endocrinol Metab, 2015 PubMed Europe PMC Scholia
  2. Sindhu S, Leung YH, Arefanian H, Madiraju SRM, Al-Mulla F, Ahmad R, Prentki M; ''Neutral sphingomyelinase-2 and cardiometabolic diseases.''; Obes Rev, 2021 PubMed Europe PMC Scholia
  3. Bar-Tana J, Rose G, Brandes R, Shapiro B; ''Palmitoyl-coenzyme A synthetase. Mechanism of reaction.''; Biochem J, 1973 PubMed Europe PMC Scholia
  4. Bellini L, Campana M, Mahfouz R, Carlier A, Véret J, Magnan C, Hajduch E, Le Stunff H; ''Targeting sphingolipid metabolism in the treatment of obesity/type 2 diabetes.''; Expert Opin Ther Targets, 2015 PubMed Europe PMC Scholia
  5. Pinter K, Grignani RT, Watkins H, Redwood C; ''Localisation of AMPK γ subunits in cardiac and skeletal muscles.''; J Muscle Res Cell Motil, 2013 PubMed Europe PMC Scholia
  6. Kaneto H, Katakami N, Matsuhisa M, Matsuoka TA; ''Role of reactive oxygen species in the progression of type 2 diabetes and atherosclerosis.''; Mediators Inflamm, 2010 PubMed Europe PMC Scholia
  7. Palomer X, Pizarro-Delgado J, Barroso E, Vázquez-Carrera M; ''Palmitic and Oleic Acid: The Yin and Yang of Fatty Acids in Type 2 Diabetes Mellitus.''; Trends Endocrinol Metab, 2018 PubMed Europe PMC Scholia
  8. Lim JH, Gerhart-Hines Z, Dominy JE, Lee Y, Kim S, Tabata M, Xiang YK, Puigserver P; ''Oleic acid stimulates complete oxidation of fatty acids through protein kinase A-dependent activation of SIRT1-PGC1α complex.''; J Biol Chem, 2013 PubMed Europe PMC Scholia
  9. Al-Rashed F, Ahmad Z, Thomas R, Melhem M, Snider AJ, Obeid LM, Al-Mulla F, Hannun YA, Ahmad R; ''Neutral sphingomyelinase 2 regulates inflammatory responses in monocytes/macrophages induced by TNF-α.''; Sci Rep, 2020 PubMed Europe PMC Scholia
  10. Miljkovic I, Yerges LM, Li H, Gordon CL, Goodpaster BH, Kuller LH, Nestlerode CS, Bunker CH, Patrick AL, Wheeler VW, Zmuda JM; ''Association of the CPT1B gene with skeletal muscle fat infiltration in Afro-Caribbean men.''; Obesity (Silver Spring), 2009 PubMed Europe PMC Scholia
  11. Kirwan JP; ''Plasma ceramides target skeletal muscle in type 2 diabetes.''; Diabetes, 2013 PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
134495view05:29, 22 July 2024EgonwRemoved a template comment
134377view15:38, 21 July 2024EweitzRemove template comments
124851view21:48, 14 December 2022EweitzModified description
124850view21:42, 14 December 2022EweitzModified title
124468view08:58, 30 October 2022EgonwTyped two translocations
124467view08:55, 30 October 2022EgonwRemoved an empty node
122326view09:01, 18 March 2022GiangNguyen126Update connection false format
122325view03:52, 18 March 2022GiangNguyen126Edit malformed references
122324view03:48, 18 March 2022GiangNguyen126Edit malformed references
122217view08:32, 16 March 2022DeSlChanged IDs for PI3K and Insulin to reviewed UniProt IDs, updated some DataNode colours to their repsective type.
122216view08:25, 16 March 2022DeSlSmall layout changes, updated legend to include non DataNodes
122214view05:05, 16 March 2022GiangNguyen126Update legend
122213view05:00, 16 March 2022GiangNguyen126Fixing connections
122191view14:05, 15 March 2022GiangNguyen126Update the interactions
122190view13:58, 15 March 2022GiangNguyen126Modified title
122189view13:55, 15 March 2022GiangNguyen126Modified description
121946view15:56, 8 March 2022GiangNguyen126Ontology Term : 'diabetes mellitus' added !
121945view15:55, 8 March 2022GiangNguyen126Ontology Term : 'obesity' added !
121944view15:54, 8 March 2022GiangNguyen126Ontology Term : 'type 2 diabetes mellitus pathway' added !
121943view15:54, 8 March 2022GiangNguyen126Ontology Term : 'atherosclerosis' added !
121942view15:48, 8 March 2022GiangNguyen126Ontology Term : 'cell of skeletal muscle' added !
121941view15:47, 8 March 2022GiangNguyen126Ontology Term : 'insulin signaling pathway' added !
121912view11:04, 8 March 2022GiangNguyen126Update Legend, color of the arrow, and incorporate feedback
121834view12:02, 7 March 2022DeSlChanged up/down regulation arrows to graphical lines, connected last unconnected line
121740view08:45, 1 March 2022GiangNguyen126Update connections, literature references
121663view07:46, 24 February 2022GiangNguyen126Update interactions
121630view14:20, 22 February 2022LucHooglugtConnected interactions
121380view08:03, 17 February 2022GiangNguyen126
121379view06:51, 17 February 2022GiangNguyen126Add in Oleic acid pathway; Add in mitochondria
121226view15:18, 12 February 2022EweitzModified description
121222view15:17, 12 February 2022EweitzModified title
121195view09:23, 11 February 2022GiangNguyen126Ceramide causes ER stress
121193view05:06, 11 February 2022GiangNguyen126Ceramide inhibits insulin promoter, update literature sources
121192view03:46, 11 February 2022GiangNguyen126Add in cell and cytokines
121172view13:37, 10 February 2022GiangNguyen126New pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ACSL1ProteinP33121 (Uniprot-TrEMBL) The activation is catalyzed by palmitoyl-coenzyme A synthetase
AKT1GeneProductENSG00000142208 (Ensembl)
AMPKProteinQ9UGI9 (Uniprot-TrEMBL)
CD36/FATProteinP16671 (Uniprot-TrEMBL)
CPT1BProteinQ92523 (Uniprot-TrEMBL)
EIF2AK2GeneProductENSG00000055332 (Ensembl) Eukaryotic Translation Initiation Factor 2 Alpha Kinase 2
ERN1ProteinO75460 (Uniprot-TrEMBL)
Fatty Acid OxidationPathwayWP143 (WikiPathways)
GLUT4 translocationPathwayWP2777 (WikiPathways)
GLUT4ProteinP14672 (Uniprot-TrEMBL)
INSRProteinP06213 (Uniprot-TrEMBL)
IRS-1ProteinP35568 (Uniprot-TrEMBL)
IRS-2ProteinQ9Y4H2 (Uniprot-TrEMBL)
InsulinProteinP01308 (Uniprot-TrEMBL)
MAFAProteinQ8NHW3 (Uniprot-TrEMBL)
MAPK8GeneProductENSG00000107643 (Ensembl)
OAMetaboliteHMDB0000207 (HMDB) Oleic acid
Oleic acidMetaboliteHMDB0000207 (HMDB)
Oxidative stress responsePathwayWP408 (WikiPathways)
PDX1GeneProductP52945 (Uniprot-TrEMBL)
PI3KProteinP27986 (Uniprot-TrEMBL) PI3K subunit alpha
PKCzetaProteinQ05513 (Uniprot-TrEMBL) Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform
PP2AProteinP67775 (Uniprot-TrEMBL) Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform
PalmitateMetaboliteCHEBI:15756 (ChEBI)
Palmitoyl-CoAMetaboliteCHEBI:15525 (ChEBI)
ROSMetabolite26523 (ChEBI)
RPS6KB1ProteinP23443 (Uniprot-TrEMBL)
Sphingolipid pathwayPathwayWP1422 (WikiPathways)
SphingomyelinMetaboliteCHEBI:89490 (ChEBI)
TNF-alphaProteinP01375 (Uniprot-TrEMBL)
TNFRProteinP19438 (Uniprot-TrEMBL)
TRAF1ProteinQ13077 (Uniprot-TrEMBL)
ceramideMetaboliteCHEBI:52639 (ChEBI)
glucoseMetaboliteCHEBI:17234 (ChEBI)
nSMase2ProteinQ9NY59 (Uniprot-TrEMBL) Sphingomyelin phosphodiesterase 2

Annotated Interactions

No annotated interactions

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