TY - JOUR
T1 - Long-chain acylcarnitines decrease the phosphorylation of the insulin receptor at tyr1151 through a ptp1b-dependent mechanism
AU - Vilks, Karlis
AU - Videja, Melita
AU - Makrecka-Kuka, Marina
AU - Katkevics, Martins
AU - Sevostjanovs, Eduards
AU - Grandane, Aiga
AU - Dambrova, Maija
AU - Liepinsh, Edgars
N1 - Funding Information:
Funding: This study was supported by a student grant from the Latvian Institute of Organic Synthesis IG-2017-03 and the Latvian Council of Science, project TRILYSOX, grant No. LZP-2018/1-0082.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/6/16
Y1 - 2021/6/16
N2 - The accumulation of lipid intermediates may interfere with energy metabolism pathways and regulate cellular energy supplies. As increased levels of long-chain acylcarnitines have been linked to insulin resistance, we investigated the effects of long-chain acylcarnitines on key components of the insulin signalling pathway. We discovered that palmitoylcarnitine induces dephosphorylation of the insulin receptor (InsR) through increased activity of protein tyrosine phosphatase 1B (PTP1B). Palmitoylcarnitine suppresses protein kinase B (Akt) phosphorylation at Ser473, and this effect is not alleviated by the inhibition of PTP1B by the insulin sensitizer bis-(maltolato)-oxovanadium (IV). This result indicates that palmitoylcarnitine affects Akt activity independently of the InsR phosphorylation level. Inhibition of protein kinase C and protein phosphatase 2A does not affect the palmitoylcarnitine-mediated inhibition of Akt Ser473 phosphorylation. Additionally, palmitoylcarnitine markedly stimulates insulin release by suppressing Akt Ser473 phosphorylation in insulin-secreting RIN5F cells. In conclusion, long-chain acylcarnitines activate PTP1B and decrease InsR Tyr1151 phosphorylation and Akt Ser473 phosphorylation, thus limiting the cellular response to insulin stimulation.
AB - The accumulation of lipid intermediates may interfere with energy metabolism pathways and regulate cellular energy supplies. As increased levels of long-chain acylcarnitines have been linked to insulin resistance, we investigated the effects of long-chain acylcarnitines on key components of the insulin signalling pathway. We discovered that palmitoylcarnitine induces dephosphorylation of the insulin receptor (InsR) through increased activity of protein tyrosine phosphatase 1B (PTP1B). Palmitoylcarnitine suppresses protein kinase B (Akt) phosphorylation at Ser473, and this effect is not alleviated by the inhibition of PTP1B by the insulin sensitizer bis-(maltolato)-oxovanadium (IV). This result indicates that palmitoylcarnitine affects Akt activity independently of the InsR phosphorylation level. Inhibition of protein kinase C and protein phosphatase 2A does not affect the palmitoylcarnitine-mediated inhibition of Akt Ser473 phosphorylation. Additionally, palmitoylcarnitine markedly stimulates insulin release by suppressing Akt Ser473 phosphorylation in insulin-secreting RIN5F cells. In conclusion, long-chain acylcarnitines activate PTP1B and decrease InsR Tyr1151 phosphorylation and Akt Ser473 phosphorylation, thus limiting the cellular response to insulin stimulation.
KW - Akt
KW - Insulin receptor
KW - Insulin resistance
KW - Long-chain acylcarnitines
KW - Palmitoylcarnitine
KW - Protein tyrosine phosphatase 1B
UR - http://www.scopus.com/inward/record.url?scp=85107852215&partnerID=8YFLogxK
U2 - 10.3390/ijms22126470
DO - 10.3390/ijms22126470
M3 - Article
C2 - 34208786
AN - SCOPUS:85107852215
SN - 1661-6596
VL - 22
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 12
M1 - 6470
ER -