MicroRNA-27a decreases the level and efficiency of the LDL receptor and contributes to the dysregulation of cholesterol homeostasis

Alvarez, M. Lucrecia; Khosroheidari, Mahdieh; Eddy, Elena; Doné, Stefania Cotta

doi:10.1016/j.atherosclerosis.2015.08.023

Cited by 84 publications

(67 citation statements)

References 52 publications

(58 reference statements)

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“…It has only been reported as a target gene of two miRNA (miR-27a and miR-124) [22, 23]. However, relationship between miR-224 and PCSK9 is still unknown.…”

Section: Discussionmentioning

confidence: 99%

A retrospective study of NENs and miR-224 promotes apoptosis of BON-1 cells by targeting PCSK9 inhibition

Bai

Hua

et al. 2016

Oncotarget

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Neuroendocrine neoplasms (NENs) represent relatively rare tumors. The lack of diagnostic, therapeutic method and prognostic factors makes them a challenge to us. We retrospectively reviewed the data of 205 NENs patients among which 157 cases were followed-up. Proprotein convertase subtilisin/kexin 9 (PCSK9), a regulator of low density lipoprotein cholesterol (LDL-C), was confirmed as a target gene of microRNA-224. We found an increased incidence of NENs from 2012 to 2015. Women were usually diagnosed at earlier stages than men (P < 0.05). Tumor grading was associated with primary tumor site, especially esophagus and cardia NENs all at G3 (P <0.001). Age, tumor grading and LDL-C levels were independent risk factors of digestive NENs. Low LDL-C level was significantly correlated with survival rate and median overall survival (OS, P < 0.05). MicroRNA-224 agomir and PCSK9 siRNA could promote apoptosis and suppress proliferation, invasion of BON-1 cells (P < 0.05), but increase the level of glucocorticoid (GC, P < 0.05). Taken together, age, tumor grading and LDL-C level are independent risk factors of NENs. The miR-224/PCSK9/GC axis binds to tumorigenesis and prognosis of pancreatic NENs (p-NENs).

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“…It has only been reported as a target gene of two miRNA (miR-27a and miR-124) [22, 23]. However, relationship between miR-224 and PCSK9 is still unknown.…”

Section: Discussionmentioning

confidence: 99%

A retrospective study of NENs and miR-224 promotes apoptosis of BON-1 cells by targeting PCSK9 inhibition

Bai

Hua

et al. 2016

Oncotarget

View full text Add to dashboard Cite

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“…Specifically, studies have identified several miRNAs that negatively regulate LDLR expression, including miR-27a/b, miR-148a, miR-128-1, miR-130b, miR-301b and miR-185. Recently it was shown that miR-27a/b regulate LDLR activity through direct targeting of the LDLR and LDLR adapter protein 1 (LDLRAP1) 57, 80 . Overexpression and inhibition of miR-27b in wild-type mice decreased and increased, hepatic LDLR expression, respectively, however no significant differences were found in circulating LDL-C or total cholesterol 57 .…”

Section: Mirna Regulation Of Ldl Metabolismmentioning

confidence: 99%

microRNAs in lipoprotein metabolism and cardiometabolic disorders

et al. 2016

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Circulating levels of low-density lipoprotein cholesterol (LDL), and high-density lipoprotein cholesterol (HDL) are two of the most important risk factors for the development of cardiovascular disease (CVD), the leading cause of death worldwide. Recently, miRNAs have emerged as critical regulators of cholesterol metabolism and promising therapeutic targets for the treatment of CVD. A great deal of work has established numerous miRNAs as important regulators of HDL metabolism. This includes miRNAs that target ABCA1, a critical factor for HDL biogenesis and reverse cholesterol transport (RCT), the process through which cells, including arterial macrophages, efflux cellular cholesterol for transport to and removal by the liver. The most well studied of these miRNAs, miR-33, has been demonstrated to target ABCA1, as well as numerous other genes involved in metabolic function and RCT, and therapeutic inhibition of miR-33 was found to increase HDL levels in mice and non-human primates. Moreover, numerous studies have demonstrated the beneficial effects of miR-33 inhibition or knockout on reducing atherosclerotic plaque burden. Even more recent work has identified miRNAs that regulate LDL cholesterol levels, including direct modulation of LDL uptake in the liver through targeting of the LDL receptor. Among these, inhibition of miR-128-1, miR-148a, or miR-185 was found to reduce plasma LDL levels, and inhibition of miR-185 was further demonstrated to reduce atherosclerotic plaque size in ApoE−/− mice. Due to their ability to target many different genes, miRNAs have the ability to mediate complex physiologic changes through simultaneous regulation of multiple interrelated pathways. Of particular importance for CVD, inhibition of miR-148a may prove an important therapeutic approach for combating dyslipidemia, as this has been demonstrated to both raise plasma HDL levels and lower LDL levels in mice by targeting both ABCA1 and LDLR, respectively. In this review we highlight recent advances in our understanding of how miRNAs regulate cholesterol metabolism and the development of atherosclerotic plaques and discuss the potential of anti-miRNA therapies for the treatment and prevention of CVD.

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“…These data suggested that a therapeutic intervention aimed at decreasing miR-27 might raise hepatic and vascular ABCA1-dependent cholesterol efflux and RCT. The interest in anti-miR-27-based therapies was enhanced by the discovery that miR-27a/b also target directly the low-density lipoprotein receptor (LDLR) and the LDLR-related genes LRP6 and LDLRAP1 [87, 89]. However, no changes in plasma total cholesterol, LDL-c or HDL-c, or in hepatic cholesterol contents were noted in mice overexpressing miR-27 via an adeno-associated virus or following therapeutic silencing with ASOs [87].…”

Section: Mirnas Targeting Hdl Biogenesis and Lipidationmentioning

confidence: 99%

miRNAs and High-Density Lipoprotein metabolism

Baldán

Vallim²

2016

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Altered lipoprotein metabolism plays a key role during atherogenesis. For over 50 years, epidemiological data have fueled the proposal that HDL-cholesterol (HDL-c) in circulation is inversely correlated to cardiovascular risk. However, the atheroprotective role of HDL is currently the focus of much debate and remains an active field of research. The emerging picture from research in the past decade suggests that HDL function, rather than HDL-c content is important in disease. Recent developments demonstrate that miRNAs play an important role in fine-tuning the expression of key genes involved in HDL biogenesis, lipidation, and clearance, as well as in determining the amounts of HDL-c in circulation. Thus, it has been proposed that miRNAs that affect HDL metabolism might be exploited therapeutically in patients. Whether HDL-based therapies, alone or in combination with LDL-based treatments (e.g. statins), provide superior outcomes in patients has been recently questioned by human genetics studies and clinical trials. The switch in focus from “HDL-cholesterol” to “HDL function” opens a new paradigm to understand the physiology and therapeutic potential of HDL, and to find novel modulators of cardiovascular risk. In this review we summarize the current knowledge on the regulation of HDL metabolism and function by miRNAs.

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MicroRNA-27a decreases the level and efficiency of the LDL receptor and contributes to the dysregulation of cholesterol homeostasis

Cited by 84 publications

References 52 publications

A retrospective study of NENs and miR-224 promotes apoptosis of BON-1 cells by targeting PCSK9 inhibition

A retrospective study of NENs and miR-224 promotes apoptosis of BON-1 cells by targeting PCSK9 inhibition

microRNAs in lipoprotein metabolism and cardiometabolic disorders

miRNAs and High-Density Lipoprotein metabolism

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