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Triciribine increases LDLR expression and LDL uptake through stabilization of LDLR mRNA.

ABSTRACT: Low-density lipoprotein receptor (LDLR) is a key regulator of the metabolism of plasma low-density lipoprotein cholesterol (LDL-C), the elevated levels of which are associated with an increased risk of cardiovascular disease. Therefore, enhancing LDLR expression represents a potent treatment strategy for hypercholesterolemia. Here, we report that in cultured human hepatoma cells, triciribine, a highly selective AKT inhibitor, increases the stability of LDLR mRNA, an event that translates into upregulation of cell-surface LDLR levels and induction of cellular LDL uptake. This effect of triciribine requires ERK activity and is partially dependent on the intervening sequence between the AU-rich elements ARE3 and ARE4 in LDLR 3'UTR. We also show that triciribine downregulates the expression of PCSK9 mRNA and blunts the secretion of its protein. Notably, triciribine was found to potentiate the effect of mevastatin on LDLR protein levels and activity. We also show that primary human hepatocytes respond to triciribine by increasing the expression of LDLR. Furthermore, a pilot experiment with mice revealed that a two-weeks treatment with triciribine significantly induced the hepatic expression of LDLR protein. These results identify triciribine as a novel LDLR-elevating agent and warrant further examination of its potential as a hypocholesterolemic drug either as monotherapy or in combination with statins.

SUBMITTER: Bjune K

PROVIDER: S-EPMC6212527 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Triciribine increases LDLR expression and LDL uptake through stabilization of LDLR mRNA.

Bjune Katrine K Wierød Lene L Naderi Soheil S

Scientific reports 20181101 1

Low-density lipoprotein receptor (LDLR) is a key regulator of the metabolism of plasma low-density lipoprotein cholesterol (LDL-C), the elevated levels of which are associated with an increased risk of cardiovascular disease. Therefore, enhancing LDLR expression represents a potent treatment strategy for hypercholesterolemia. Here, we report that in cultured human hepatoma cells, triciribine, a highly selective AKT inhibitor, increases the stability of LDLR mRNA, an event that translates into up ...[more]

PMID: 30385871

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Project description:Proprotein convertase subtilisin/kexin type 9 (PCSK9) can promote the degradation of low-density lipoprotein (LDL) receptor (LDLR), leading to hypercholesterolemia and myocardial dysfunction. The intracellular regulatory mechanism by which the natural polyphenol pterostilbene modulates the PCSK9/LDLR signaling pathway in cardiomyocytes has not been evaluated. We conducted Western blotting, flow cytometry, immunofluorescence staining, and mean fluorescence intensity analyses of pterostilbene-treated mouse HL-1 cardiomyocytes. Pterostilbene did not alter cardiomyocyte viability. Compared to the control group, treatment with both 2.5 and 5 μM pterostilbene significantly increased the LDLR protein expression accompanied by increased uptake of LDL. The expression of the mature PCSK9 was significantly suppressed at the protein and mRNA level by the treatment with both 2.5 and 5 μM pterostilbene, respectively, compared to the control. Furthermore, 2.5 and 5 μM pterostilbene treatment resulted in a significant reduction in the protein hepatic nuclear factor 1α (HNF1α)/histone deacetylase 2 (HDAC2) ratio and sterol regulatory element-binding protein-2 (SREBP2)/HDAC2 ratio. The expression of both hypoxia-inducible factor-1 α (HIF1α) and nuclear factor erythroid 2-related factor 2 (Nrf2) at the protein level was also suppressed. Pterostilbene as compared to short hairpin RNA against SREBP2 induced a higher protein expression of LDLR and lower nuclear accumulation of HNF1α and SREBP2. In addition, pterostilbene reduced PCSK9/SREBP2 interaction and mRNA expression by increasing the expression of hsa-miR-335 and hsa-miR-6825, which, in turn, increased LDLR mRNA expression. In cardiomyocytes, pterostilbene dose-dependently decreases and increases the protein and mRNA expression of PCSK9 and LDLR, respectively, by suppressing four transcription factors, HNF1α, SREBP2, HIF1α, and Nrf2, and enhancing the expression of hsa-miR-335 and hsa-miR-6825, which suppress PCSK9/SREBP2 interaction.

Dataset Information

Triciribine increases LDLR expression and LDL uptake through stabilization of LDLR mRNA.

Publications

Triciribine increases LDLR expression and LDL uptake through stabilization of LDLR mRNA.

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