BBA - Molecular and Cell Biology of Lipids (v.1861, #12PB)

Preface to: “microRNAs in lipid/energy metabolism and cardiometabolic disease” by Yajaira Suárez; Carlos Fernández-Hernando (2039-2040).

miRNA and cholesterol homeostasis by Tae-Il Jeon; Timothy F. Osborne (2041-2046).
MicroRNAs (miRNAs) have recently emerged as a novel class of epigenetic regulators of gene expression. They are systemically involved in the control of lipid metabolism through a complex interactive mechanism that involves gene regulatory networks. Hence, they can contribute to defective lipid metabolism and metabolic diseases. Here, we review recent advances in the roles of lipid-sensing transcription factors in regulating miRNA gene networks, as well as miRNA expression and function in the regulation of cholesterol metabolism. This article is part of a Special Issue entitled: MicroRNAs and lipid/energy metabolism and related diseases edited by Carlos Fernández-Hernando and Yajaira Suárez
Keywords: MicroRNA; Cholesterol metabolism; Transcription factor; Metabolic disease;

miRNA regulation of LDL-cholesterol metabolism by Leigh Goedeke; Alexandre Wagschal; Carlos Fernández-Hernando; Anders M. Näär (2047-2052).
In the past decade, microRNAs (miRNAs) have emerged as key regulators of circulating levels of lipoproteins. Specifically, recent work has uncovered the role of miRNAs in controlling the levels of atherogenic low-density lipoprotein LDL (LDL)-cholesterol by post-transcriptionally regulating genes involved in very low-density lipoprotein (VLDL) secretion, cholesterol biosynthesis, and hepatic LDL receptor (LDLR) expression. Interestingly, several of these miRNAs are located in genomic loci associated with abnormal levels of circulating lipids in humans. These findings reinforce the interest of targeting this subset of non-coding RNAs as potential therapeutic avenues for regulating plasma cholesterol and triglyceride (TAG) levels. In this review, we will discuss how these new miRNAs represent potential pre-disposition factors for cardiovascular disease (CVD), and putative therapeutic targets in patients with cardiometabolic disorders. This article is part of a Special Issue entitled: MicroRNAs and lipid/energy metabolism and related diseases edited by Carlos Fernández-Hernando and Yajaira Suárez.
Keywords: miRNA; LDL; cholesterol; LDLR; lipid; GWAS;

miRNAs and High-Density Lipoprotein metabolism by Ángel Baldán; Thomas Q. de Aguiar Vallim (2053-2061).
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. This article is part of a Special Issue entitled: MicroRNAs and lipid/energy metabolism and related diseases edited by Carlos Fernández-Hernando and Yajaira Suárez.
Keywords: miRNA; HDL; Lipoproteins; Cholesterol; Atherosclerosis; Cardiovascular disease;

MicroRNAs regulating apolipoprotein B-containing lipoprotein production by Liye Zhou; Sara Irani; Alaa Sirwi; M. Mahmood Hussain (2062-2068).
MicroRNAs (miRs) are small, non-coding RNAs that regulate gene expression and have been implicated in many pathological conditions. Significant progress has been made to unveil their role in lipid metabolism. This review aims at summarizing the role of different miRs that regulate hepatic assembly and secretion of apolipoprotein B (apoB)-containing lipoproteins. Overproduction and/or impaired clearance of these lipoproteins from circulation increase plasma concentrations of lipids enhancing risk for cardiovascular disease. So far, three miRs, miR-122, miR-34a, and miR-30c have been shown to modulate hepatic production of apoB-containing low density lipoproteins. In this review, we will first provide a brief overview of lipid metabolism and apoB-containing lipoprotein assembly to orient readers to different steps that have been shown to be regulated by miRs. Then, we will discuss the role of each miR on plasma lipids and atherosclerotic burden. Furthermore, we will summarize mechanistic studies explaining how these miRs regulate hepatic lipid synthesis, fatty acid oxidation, and lipoprotein secretion. Finally, we will briefly highlight the potential use of each miR as a therapeutic drug for treating cardiovascular diseases. This article is part of a Special Issue entitled: MicroRNAs and lipid/energy metabolism and related diseases edited by Carlos Fernández-Hernando and Yajaira Suárez.Display Omitted
Keywords: MicroRNA; Cholesterol; Triglyceride; Hyperlipidemia; Hepatosteatosis; Atherosclerosis;

Lipoprotein carriers of microRNAs by Danielle L. Michell; Kasey C. Vickers (2069-2074).
Lipoproteins, namely high-density lipoproteins (HDL), transport a wide-variety of cargo in addition to cholesterol and lipids. In 2011, HDL and low-density lipoproteins (LDL) were reported to transport microRNAs (miRNA). Since the original discovery, there has been great excitement for this topic and a handful of follow-up publications. Here, we review the current landscape of lipoprotein transport of miRNAs. HDL-miRNAs have been demonstrated to be altered in cardiovascular disease (CVD), including hypercholesterolemia and atherosclerosis. As such, HDL- and LDL-miRNAs may represent a novel class of disease biomarkers. Below, we review HDL-miR-92a and miR-486 levels in myocardial infarction and unstable angina, and HDL-miR-223 and miR-24 levels in coronary artery disease (CAD). Moreover, we address HDL's contribution to the total pool of extracellular miRNAs in plasma and differential distribution of miRNAs across HDL subspecies. Finally, we address current and future challenges for this new field and the barriers to such work. This article is part of a Special Issue entitled: MicroRNAs and lipid/energy metabolism and related diseases edited by Carlos Fernández-Hernando and Yajaira Suárez.
Keywords: microRNA; Extracellular microRNA; Lipoproteins; HDL;

Small but smart: MicroRNAs orchestrate atherosclerosis development and progression by Donato Santovito; Virginia Egea; Christian Weber (2075-2086).
MicroRNAs (miRNAs) are short non-coding RNA able to bind specific sequences on target messenger RNAs (mRNAs) and thereby to post-transcriptionally modulate gene expression. Being expressed in all vertebrate cell types, miRNAs have emerged as key players in a wide array of biological processes, including cell proliferation, differentiation and apoptosis. Over the past decade, knowledge concerning the contribution of miRNAs to human pathology has grown with an astonishing pace. In particular, a major involvement of miRNAs in atherosclerosis as a leading cause of global mortality has been supported by ample evidence from in vitro, in vivo and clinical studies. This review aims to summarize and highlight current concepts of miRNA function in the continuum of atherogenesis ranging from risk factors (i.e. dyslipidemia, diabetes, hypertension), to endothelial dysfunction up to the events leading to plaque rupture. Areas in need for further research and potential perspectives for translational applications will be scrutinized. This article is part of a Special Issue entitled: MicroRNAs and lipid/energy metabolism and related diseases edited by Carlos Fernández-Hernando and Yajaira Suárez.
Keywords: Atherosclerosis; MicroRNAs; Inflammation; Endothelium; Macrophage; Smooth muscle cell;

Macrophage miRNAs in atherosclerosis by Denuja Karunakaran; Katey J. Rayner (2087-2093).
The discovery of endogenous microRNAs (miRNAs) in the early 1990s has been followed by the identification of hundreds of miRNAs and their roles in regulating various biological processes, including proliferation, apoptosis, lipid metabolism, glucose homeostasis and viral infection Esteller (2011), Ameres and Zamore (2013) [1,2]. miRNAs are small (~ 22 nucleotides) non-coding RNAs that function as “rheostats” to simultaneously tweak the expression of multiple genes within a genetic network, resulting in dramatic functional modulation of biological processes. Although the last decade has brought the identification of miRNAs, their targets and function(s) in health and disease, there remains much to be deciphered from the human genome and its complexities in mechanistic regulation of entire genetic networks. These discoveries have opened the door to new and exciting avenues for therapeutic interventions to treat various pathological diseases, including cardiometabolic diseases such as atherosclerosis, diabetes and obesity. In a complex multi-factorial disease like atherosclerosis, many miRNAs have been shown to contribute to disease progression and may offer novel targets for future therapy. This article is part of a Special Issue entitled: MicroRNAs and lipid/energy metabolism and related diseases edited by Carlos Fernández-Hernando and Yajaira Suárez.
Keywords: MicroRNA; Macrophage; Cholesterol efflux; Atherosclerosis; Inflammation; Therapeutic;

Endothelial cells (ECs) provide nutrients and oxygen essential for tissue homeostasis. Metabolic imbalances and other environmental stimuli, like cytokines or low shear stress, trigger endothelial inflammation, increase permeability, compromise vascular tone, promote cell proliferation, and ultimately cause cell death. These factors contribute to EC dysfunction, which is crucial in the development of cardiometabolic diseases. microRNAs (miRNAs) are small non-coding RNAs that have important functions in the regulation of ECs. In the present review, we discuss the role of miRNAs in various aspects of EC pathology in cardiometabolic diseases like atherosclerosis, type 2 diabetes, obesity, and the metabolic syndrome, and in complication of those pathologies, like ischemia. We also discuss the potential therapeutic applications of miRNAs in promoting angiogenesis and neovascularization in tissues where the endothelium is damaged in different cardiometabolic diseases. This article is part of a Special Issue entitled: MicroRNAs and lipid/energy metabolism and related diseases edited by Carlos Fernández-Hernando and Yajaira Suárez.
Keywords: Endothelial cells; Metabolic syndrome; MicroRNAs; Atherosclerosis; Type 2 diabetes; Cardiovascular disease;

miRNA regulation of white and brown adipose tissue differentiation and function by Nathan L. Price; Carlos Fernández-Hernando (2104-2110).
Obesity and metabolic disorders are a major health concern in all developed countries and a primary focus of current medical research is to improve our understanding treatment of metabolic diseases. One avenue of research that has attracted a great deal of recent interest focuses upon understanding the role of miRNAs in the development of metabolic diseases. miRNAs have been shown to be dysregulated in a number of different tissues under conditions of obesity and insulin resistance, and have been demonstrated to be important regulators of a number of critical metabolic functions, including insulin secretion in the pancreas, lipid and glucose metabolism in the liver, and nutrient signaling in the hypothalamus. In this review we will focus on the important role of miRNAs in regulating the differentiation and function of white and brown adipose tissue and the potential importance of this for maintaining metabolic function and treating metabolic diseases. This article is part of a Special Issue entitled: MicroRNAs and lipid/energy metabolism and related diseases edited by Carlos Fernández-Hernando and Yajaira Suárez.
Keywords: miRNA; WAT; BAT; Adipogenesis; Obesity; Metabolic syndrome;

MicroRNA transport in cardiovascular complication of diabetes by Andrea Caporali; Vladislav Miscianinov; Jaimy Saif; Costanza Emanueli (2111-2120).
MicroRNAs (miRNAs) are post-transcriptional inhibitory regulators of gene expression by binding to complementary messenger RNA (mRNA) transcripts. Extracellular miRNAs are transported by membrane-derived vesicles (exosomes and microparticles), lipoproteins, and other ribonucleoprotein complexes. Extracellular microRNAs are emerging as important mediators of intercellular communications, being involved in the transmission of biological signals between cells. Several miRNAs have been identified as having a primary impact on many biological processes that are of direct relevance to cardiovascular complications of diabetes. Whether the extracellular miRNAs are directly involved in the regulation of these processes is yet to be established. Here, we review recent progresses in extracellular miRNA biology and the role of extracellular miRNA in diabetes induced cardiovascular disease, describing the regulators affecting miRNA transport and the mechanisms for different miRNA transporters. In addition, we discuss the advancement of the research in this field and identify the associated challenges. This article is part of a Special Issue entitled: MicroRNAs and lipid/energy metabolism and related diseases edited by Carlos Fernández-Hernando and Yajaira Suárez.
Keywords: MicroRNAs; Extracellular vesicles; Exosomes; Diabetes; Cardiovascular disease;

New emerging tasks for microRNAs in the control of β-cell activities by Claudiane Guay; Romano Regazzi (2121-2129).
MicroRNAs are key regulators of β-cell physiology. They participate to the differentiation of insulin-producing cells and are instrumental for the acquisition of their unique secretory properties. Moreover, they contribute to the adaptation of β-cells to conditions of increased insulin demand and, if expressed at inappropriate levels, certain microRNAs cause β-cell dysfunction and promote the development of different forms of diabetes mellitus. While these functions are increasingly better understood, additional tasks for these small non-coding RNAs have been recently unveiled. Thus, microRNAs are emerging as signaling molecules of a novel exosome-mediated cell-to-cell communication mode permitting a coordinated response of the β-cells to inflammatory conditions and to modifications in the insulin demand. These discoveries raise a number of important issues that once addressed promise to shed new light on the molecular mechanism governing the functions of the β-cells under normal and disease states. This article is part of a Special Issue entitled: MicroRNAs and lipid/energy metabolism and related diseases edited by Carlos Fernández-Hernando and Yajaira Suárez.
Keywords: Islet; Insulin; Diabetes; MicroRNA; Exosome;

microManaging glucose and lipid metabolism in skeletal muscle: Role of microRNAs by Julie Massart; Mutsumi Katayama; Anna Krook (2130-2138).
MicroRNAs have been described as important regulators of skeletal muscle differentiation and development, but the role of microRNAs in glucose and lipid metabolism is less well established. Here we review the microRNAs involved in insulin resistance and glucose metabolism, as well as microRNAs regulating lipid metabolism and mitochondrial functions in skeletal muscle, with an emphasis on metabolic disorders such as type 2 diabetes and the adaptive response to exercise training. Finally, we raise some methodological considerations for studying microRNAs, as well as challenges investigators may face when elucidating the direct role of microRNAs in the regulation of glucose and lipid metabolism in skeletal muscle. This article is part of a Special Issue entitled: MicroRNAs and lipid/energy metabolism and related diseases edited by Carlos Fernández-Hernando and Yajaira Suárez.
Keywords: microRNA; Skeletal muscle; Type 2 diabetes; Metabolism; Exercise;

Cholesterol is important for various neuronal functions in the brain. Brain has elaborate regulatory mechanisms to control cholesterol metabolism that are distinct from the mechanisms in periphery. Interestingly, dysregulation of the cholesterol metabolism is strongly associated with a number of neurodegenerative diseases. MicroRNAs are short non-coding RNAs acting as post-transcriptional gene regulators. Recently, several microRNAs are demonstrated to be involved in regulating cholesterol metabolism in the brain. This article reviews the regulatory mechanisms of cellular cholesterol homeostasis in the brain. In addition, we discuss the role of microRNAs in brain cholesterol metabolism and their potential implications for the treatment of Alzheimer's disease. This article is part of a special issue entitled: MicroRNAs and lipid/energy metabolism and related diseases edited by Carlos Fernández-Hernando and Yajaira Suárez.Display Omitted
Keywords: MicroRNA; Lipid metabolism; Cholesterol metabolism; Central nervous system; Alzheimer's disease;