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.

Inhibitors of AKT kinase increase LDL receptor mRNA expression by two different mechanisms

“…To examine the effect of these inhibitors on LDLR gene transcription, we cultured HepG2 cells that were transfected with the pLR1563-luc plasmid, a luciferase reporter construct driven by the LDLR promoter, in the absence or presence of the AKT inhibitors for 14 h and then examined them for luciferase activity. As expected, luciferase activity was induced in cells that were treated with MK-2206, whereas triciribine had no effect on luciferase activity (Fig 2B) [16, 17]. Interestingly, all the other AKT inhibitors also exerted a positive effect on luciferase activity.…”

“…We have recently shown that two pharmacologic inhibitors of AKT, MK-2206 and triciribine, increase the levels of LDLR mRNA, leading to increased levels of cell-surface LDLRs [16, 17]. Interestingly, we found that MK-2206 and triciribine utilize two different regulatory mechanisms to trigger the accumulation of LDLR mRNA.…”

Triciribine Engages ZFP36L1 and HuR to Stabilize LDLR mRNA

“…Small molecule-induced stabilization of LDLR mRNA represents a very attractive approach to increase LDLR protein expression in order to treat hypercholesterolemia. Previous studies reported that the LDLR mRNA is labile, but that it can be stabilized in the presence of different small molecule compounds, such as berberine [ 5 ], canadine [ 11 ], AICAR [ 14 ], gemfibrozil [ 29 ], chenodeoxycholic acid [ 8 ] and triciribine [ 12 ]. While the mechanism of LDLR mRNA stabilization by canadine and gemfibrozil is still unknown, triciribine (TCN) shares similarities to berberine, AICAR, and chenodeoxycholic acid by stabilizing LDLR mRNA through an ERK1/2-dependent pathway, and involve the LDLR 3′UTR [ 5 , 8 , 12 , 14 ].…”

“…Recently, it was reported that TCN increases LDLR levels by preventing the degradation of LDLR mRNA in an ERK activity-dependent manner [ 12 ]. This work aimed to elucidate the mechanism that underlies this property of TCN.…”

USP16 Regulates the Stability and Function of LDL receptor by Deubiquitination

“…12) Simultaneously, ubiquitin-USP16 REGULATES THE STABILITY AND FUNCTION OF LDLR specific protease (USP) 2, one of the deubiquitinating enzyme (DUB), regulates the LDLR pathway by counteracting the E3-ubiquitin ligase IDOL. [13][14][15][16] However, regulation of deubiquitylases in cholesterol metabolism has remained elusive. The widespread pathogenicity of LDL is urgently required for a better understanding of this mechanism, as well as exploring new therapeutic approaches.…”