Roles of ceramides in development of insulin resistance (WP5181)

Homo sapiens

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.

Authors

Giang Nguyen , Eric Weitz , Luc Hooglugt , Denise Slenter , and Egon Willighagen

Activity

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Organisms

Homo sapiens

Communities

Annotations

Disease Ontology

diabetes mellitus atherosclerosis obesity

Cell Type Ontology

cell of skeletal muscle

Pathway Ontology

type 2 diabetes mellitus pathway insulin signaling pathway

Participants

Label Type Compact Identifier Comment
ROS Metabolite chebi:26523
Palmitate Metabolite chebi:15756
Sphingomyelin Metabolite chebi:89490
ceramide Metabolite chebi:52639
Palmitoyl-CoA Metabolite chebi:15525
glucose Metabolite chebi:17234
Oleic acid Metabolite hmdb:HMDB0000207
OA Metabolite hmdb:HMDB0000207 Oleic acid
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Palmitate Metabolite chebi:15756
MAPK8 GeneProduct ensembl:ENSG00000107643
AKT1 GeneProduct ensembl:ENSG00000142208
EIF2AK2 GeneProduct ensembl:ENSG00000055332 Eukaryotic Translation Initiation Factor 2 Alpha Kinase 2
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PDX1 GeneProduct uniprot:P52945
TRAF1 Protein uniprot:Q13077
CPT1B Protein uniprot:Q92523
RPS6KB1 Protein uniprot:P23443
ACSL1 Protein uniprot:P33121 The activation is catalyzed by palmitoyl-coenzyme A synthetase
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TNFR Protein uniprot:P19438
CD36/FAT Protein uniprot:P16671
GLUT4 Protein uniprot:P14672
ERN1 Protein uniprot:O75460
IRS-1 Protein uniprot:P35568
IRS-2 Protein uniprot:Q9Y4H2
INSR Protein uniprot:P06213
PP2A Protein uniprot:P67775 Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform
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PKCzeta Protein uniprot:Q05513 Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform
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TNF-alpha Protein uniprot:P01375
PI3K Protein uniprot:P27986 PI3K subunit alpha
MAFA Protein uniprot:Q8NHW3
Insulin Protein uniprot:P01308
nSMase2 Protein uniprot:Q9NY59 Sphingomyelin phosphodiesterase 2
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AMPK Protein uniprot:Q9UGI9
IRS-1 Protein uniprot:P35568
IRS-2 Protein uniprot:Q9Y4H2

References

  1. Palmitoyl-coenzyme A synthetase. Mechanism of reaction. Bar-Tana J, Rose G, Brandes R, Shapiro B. Biochem J. 1973 Feb;131(2):199–209. PubMed Europe PMC Scholia
  2. Association of the CPT1B gene with skeletal muscle fat infiltration in Afro-Caribbean men. Miljkovic I, Yerges LM, Li H, Gordon CL, Goodpaster BH, Kuller LH, et al. Obesity (Silver Spring). 2009 Jul;17(7):1396–401. PubMed Europe PMC Scholia
  3. Role of reactive oxygen species in the progression of type 2 diabetes and atherosclerosis. Kaneto H, Katakami N, Matsuhisa M, Matsuoka T aki. Mediators Inflamm. 2010;2010:453892. PubMed Europe PMC Scholia
  4. Oleic acid stimulates complete oxidation of fatty acids through protein kinase A-dependent activation of SIRT1-PGC1α complex. Lim JH, Gerhart-Hines Z, Dominy JE, Lee Y, Kim S, Tabata M, et al. J Biol Chem. 2013 Mar 8;288(10):7117–26. PubMed Europe PMC Scholia
  5. Plasma ceramides target skeletal muscle in type 2 diabetes. Kirwan JP. Diabetes. 2013 Feb;62(2):352–4. PubMed Europe PMC Scholia
  6. Localisation of AMPK γ subunits in cardiac and skeletal muscles. Pinter K, Grignani RT, Watkins H, Redwood C. J Muscle Res Cell Motil. 2013 Dec;34(5–6):369–78. PubMed Europe PMC Scholia
  7. Targeting sphingolipid metabolism in the treatment of obesity/type 2 diabetes. Bellini L, Campana M, Mahfouz R, Carlier A, Véret J, Magnan C, et al. Expert Opin Ther Targets. 2015;19(8):1037–50. PubMed Europe PMC Scholia
  8. Targeting endoplasmic reticulum stress in insulin resistance. Salvadó L, Palomer X, Barroso E, Vázquez-Carrera M. Trends Endocrinol Metab. 2015 Aug;26(8):438–48. PubMed Europe PMC Scholia
  9. Palmitic and Oleic Acid: The Yin and Yang of Fatty Acids in Type 2 Diabetes Mellitus. Palomer X, Pizarro-Delgado J, Barroso E, Vázquez-Carrera M. Trends Endocrinol Metab. 2018 Mar;29(3):178–90. PubMed Europe PMC Scholia
  10. Neutral sphingomyelinase 2 regulates inflammatory responses in monocytes/macrophages induced by TNF-α. Al-Rashed F, Ahmad Z, Thomas R, Melhem M, Snider AJ, Obeid LM, et al. Sci Rep. 2020 Oct 8;10(1):16802. PubMed Europe PMC Scholia
  11. Neutral sphingomyelinase-2 and cardiometabolic diseases. Sindhu S, Leung YH, Arefanian H, Madiraju SRM, Al-Mulla F, Ahmad R, et al. Obes Rev. 2021 Aug;22(8):e13248. PubMed Europe PMC Scholia