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L-carnitine increases cell proliferation and amino acid transporter expression via the activation of insulin-like growth factor I signaling pathway in rat trophoblast cells.

ABSTRACT: Early embryo implantation and development is primarily determined by the homeostasis between cellular apoptosis and proliferation as well as placental nutrient transporters. Recent studies showed that L-carnitine enhances female reproductive performance. However, the potential function of L-carnitine on placenta is largely unknown. In our study, primary rat trophoblast cells were separated and cultured for 12 hr in medium containing various concentrations of L-carnitine (0, 1, 10, and 50 mM). Placenta trophoblast cells treated with 50 mM L-carnitine increased the proportion of cells in S phase of the cell cycle (p < .05). In addition, live cell percentage was increased when treated with either 10 mM or 50 mM L-carnitine, which was accompanied with decreased necrotic cells, late apoptotic cells, and early apoptotic cells (p < .05). Compared with the control treatment, the mRNA expression of insulin-like growth factor I (IGF-1) and insulin-like growth factor I receptor (IGF-1R) was higher in rat placenta trophoblasts treated with either 10 mM or 50 mM L-carnitine (p < .05). Similarly, sodium-dependent neutral amino acid transporter (SNAT)-1 and SNAT2 were up-regulated in both mRNA and protein levels when trophoblast cells were treated with 50 mM L-carnitine (p < .05). Inhibiting downstream targets (Akt or ERK signaling pathways) of IGF-1 signaling pathway partially blocked the effect the L-carnitine-induced increase in protein abundances of SNAT1 and SNAT2. Collectively, our data showed protective role of L-carnitine on placenta trophoblast cells through the involvement of IGF-1 signaling pathway.

SUBMITTER: Zhang S

PROVIDER: S-EPMC7382193 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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L-carnitine increases cell proliferation and amino acid transporter expression via the activation of insulin-like growth factor I signaling pathway in rat trophoblast cells.

Zhang Shihai S Wu Zhihui Z Heng Jinghui J Tian Min M Chen Jiaming J Chen Fang F Guan Wutai W

Food science & nutrition 20200428 7

Early embryo implantation and development is primarily determined by the homeostasis between cellular apoptosis and proliferation as well as placental nutrient transporters. Recent studies showed that L-carnitine enhances female reproductive performance. However, the potential function of L-carnitine on placenta is largely unknown. In our study, primary rat trophoblast cells were separated and cultured for 12 hr in medium containing various concentrations of L-carnitine (0, 1, 10, and 50 mM). Pl ...[more]

PMID: 32724594

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Project description:Aims/hypothesisSodium-glucose cotransporter 2 (SGLT2) inhibitors, which prevent the renal reabsorption of glucose, decrease blood glucose levels in an insulin-independent manner. We previously reported creating a mouse model of systemic inhibition of target receptors for both insulin and IGF-1 by treating animals with OSI-906, a dual insulin/IGF-1 receptor inhibitor, for 7 days. The OSI-906-treated mice exhibited an increased beta cell mass, hepatic steatosis and adipose tissue atrophy, accompanied by hyperglycaemia and hyperinsulinaemia. In the present study, we investigated the effects of an SGLT2 inhibitor, luseogliflozin, on these changes in OSI-906-treated mice.MethodsWe treated C57BL/6J male mice either with vehicle, luseogliflozin, OSI-906 or OSI-906 plus luseogliflozin for 7 days, and phenotyping was performed to determine beta cell mass and proliferation. Subsequently, we tested whether serum-derived factors have an effect on beta cell proliferation in genetically engineered beta cells, mouse islets or human islets.ResultsSGLT2 inhibition with luseogliflozin significantly ameliorated hyperglycaemia, but not hyperinsulinaemia, in the OSI-906-treated mice. Liver steatosis and adipose tissue atrophy induced by OSI-906 were not altered by treatment with luseogliflozin. Beta cell mass and proliferation were further increased by SGLT2 inhibition with luseogliflozin in the OSI-906-treated mice. Luseogliflozin upregulated gene expression related to the forkhead box M1 (FoxM1)/polo-like kinase 1 (PLK1)/centromere protein A (CENP-A) pathway in the islets of OSI-906-treated mice. The increase in beta cell proliferation was recapitulated in a co-culture of Irs2 knockout and Insr/IR knockout (βIRKO) beta cells with serum from both luseogliflozin- and OSI-906-treated mice, but not after SGLT2 inhibition in beta cells. Circulating factors in both luseogliflozin- and OSI-906-treated mice promoted beta cell proliferation in both mouse islets and cadaveric human islets.Conclusions/interpretationThese results suggest that luseogliflozin can increase beta cell proliferation through the activation of the FoxM1/PLK1/CENP-A pathway via humoral factors that act in an insulin/IGF-1 receptor-independent manner.

Dataset Information

L-carnitine increases cell proliferation and amino acid transporter expression via the activation of insulin-like growth factor I signaling pathway in rat trophoblast cells.

Publications

L-carnitine increases cell proliferation and amino acid transporter expression via the activation of insulin-like growth factor I signaling pathway in rat trophoblast cells.

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