Abstract
Aberrant regulation of cholesterol homeostasis is associated with obesity as well as multiple types of cancer. However, the mechanism behind these is largely missing. Here, we show that microRNA (miRNA)-128-2 is not only a pro-apoptotic microRNA but it also alters the expression of genes involved in cellular cholesterol homeostasis. Cholesterol efflux via ATP-binding cassette transporters (ABCA1 and ABCG1) is a mechanism for cells to eliminate excess cholesterol and prevent cellular cholesterol accumulation. The regulation of these pathways is complex with transcriptional regulation by sterol-regulatory element-binding protein (SREBP) and liver X receptor/retinoid X receptor (RXR) transcription factors but poorly understood at the post-transcriptional levels. MiR-128-2 increases the expression of SREBP2 and decreases the expression of SREBP1 in HepG2, MCF7 and HEK293T cells independent of sirtuin 1 (SIRT1) status. MiR-128-2 inhibits the expression of ABCA1, ABCG1 and RXRα directly through a miR-128-2-binding site within their respective 3′untranslated regions. The administration of miR-128-2 leads to decline in the protein and mRNA levels of ABCA1, ABCG1 and RXRα. Conversely, anti-miRNA treatment leads to increased ABCA1, ABCG1 and RXRα expression. The inverse correlation between miR-128-2 and its targets viz. ABCA1 and ABCG1 was also established during high-fat diet in different mice tissues. Our data show that cholesterol efflux is attenuated by miR-128-2 overexpression and, conversely, stimulated by miR-128-2 silencing. Further, we also observed the induction of ER stress response by miR-128-2. In this study, we provide the first evidence of miR-128-2 to be a new regulator of cholesterol homeostasis. Our study shows dual role of miR-128-2, as a pro-apoptotic molecule as well as a regulator of cholesterol homeostasis.
Highlights
Cholesterol levels are maintained through a tightly regulated and complex mechanism that includes the de novo biosynthesis, internalization of exogenous cholesterol and efflux of excess cholesterol
We showed that miR-128-2 directly targets ABC transporters (ABCA1 and ABCG1) and RXRa and regulates cellular cholesterol efflux
We have shown that miR-128-2 induces apoptosis in a p53-dependent and -independent manner by downregulation of SIRT1.28 Literature reveals that SIRT1, a NAD-dependant deacetylase, is a key regulator of energy homeostasis and has a role in lipid and glucose metabolism
Summary
Cholesterol levels are maintained through a tightly regulated and complex mechanism that includes the de novo biosynthesis, internalization of exogenous cholesterol and efflux of excess cholesterol. These mechanisms are regulated by transcription factors such as sterol-regulatory elementbinding protein (SREBPs) and Liver X receptors (LXRs). The SREBP transcription factors regulate the expression of genes involved in cholesterol biosynthesis and cellular uptake.[12] LXR/retinoid X receptor (RXR) functions as a sensor of cellular cholesterol concentration and mediates cholesterol efflux by inducing the transcription of key cholesterol shuffling vehicles namely, ATP-binding cassette transporters (ABCA1 and ABCG1) and apolipoprotein E and maintains cellular sterol homeostasis.[13,14]. We identified that miR-128-2 is a pro-apoptotic molecule but is a regulator of cholesterol metabolism, might be opening new avenues for the treatment of diseases besides cancer
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