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

Abstract

Protein kinase B (AKT) is a serine/threonine kinase that functions as an important downstream effector of phosphoinositide 3-kinase. We have recently shown that MK-2206 and triciribine, two highly selective AKT inhibitors increase the level of low density lipoprotein receptor (LDLR) mRNA which leads to increased amount of cell-surface LDLRs. However, whereas MK-2206 induces transcription of the LDLR gene, triciribine stabilizes LDLR mRNA, raising the possibility that the two inhibitors may actually affect other kinases than AKT. In this study, we aimed to ascertain the role of AKT in regulation of LDLR mRNA expression by examining the effect of five additional AKT inhibitors on LDLR mRNA levels. Here we show that in cultured HepG2 cells, AKT inhibitors ARQ-092, AKT inhibitor VIII, perifosine, AT7867 and CCT128930 increase LDLR mRNA levels by inducing the activity of LDLR promoter. CCT128930 also increased the stability of LDLR mRNA. To study the role of AKT isoforms on LDLR mRNA levels, we examined the effect of siRNA-mediated knockdown of AKT1 or AKT2 on LDLR promoter activity and LDLR mRNA stability. Whereas knockdown of either AKT1 or AKT2 led to upregulation of LDLR promoter activity, only knockdown of AKT2 had a stabilizing effect on LDLR mRNA. Taken together, these results provide strong evidence for involvement of AKT in regulation of LDLR mRNA expression, and point towards the AKT isoform specificity for upregulation of LDLR mRNA expression.

Resveratrol Regulates Glucose and Lipid Metabolism in Diabetic Rats by Inhibition of PDK1/AKT Phosphorylation and HIF-1α Expression

“… 49 The reduction in active SREBP-2 results in a decrease in LDLR protein level, owing to the reduced binding of SREBP-2 to the cognate sterol regulatory element-1 (SRE-1) in the LDLR promoter. 50 These findings suggested that LDLR might act downstream of the HIF-1α pathway. Furthermore, silencing of HIF-1α was found to increase LDLR levels in HepG2 cells stimulated with oleic acid and palmitic acid.…”

PCSK9 dysregulates cholesterol homeostasis and triglyceride metabolism in olanzapine‐induced hepatic steatosis via both receptor‐dependent and receptor‐independent pathways

“…It should be noted that LDLR and CD36 gene expressions were markedly upregulated by olanzapine treatment, suggesting that olanzapine can regulate LDLR and CD36 at the transcriptional level, independently of its post‐translational effects via the PCSK9 pathway. Inhibitors of protein kinase B (Akt) increase LDLR expression through extracellular signal‐regulated kinase (ERK)‐dependent stabilization of LDLR mRNA, 34,35 and proliferative and neuroprotective effects of olanzapine in vitro appear to be mediated by activation of PI3K/Akt and ERK pathways in PC12 cells 36 . In addition, it has been reported that the hepatic mTOR signaling pathway is enhanced in olanzapine‐induced dyslipidemia 37 and plays a crucial role in regulating lipid biosynthesis and lipogenesis via peroxisome proliferator‐activated receptor gamma (PPARγ), 38 a key regulator of CD36 38–40 .…”

Flavonoids regulate LDLR through different mechanisms tied to their specific structures

“…We have previously demonstrated that two pharmacologic inhibitors of the protein kinase AKT, MK-2206 and triciribine, increase LDLR mRNA levels by two different mechanisms ( 32 , 38 , 39 ). MK-2206 stimulates LDLR expression by inducing the proteolytic activation of SREBP2, while triciribine enhances LDLR mRNA stability.…”