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      MicroRNAs in metabolism

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          Abstract

          Micro RNAs (mi RNAs) have within the past decade emerged as key regulators of metabolic homoeostasis. Major tissues in intermediary metabolism important during development of the metabolic syndrome, such as β‐cells, liver, skeletal and heart muscle as well as adipose tissue, have all been shown to be affected by mi RNAs. In the pancreatic β‐cell, a number of mi RNAs are important in maintaining the balance between differentiation and proliferation (miR‐200 and miR‐29 families) and insulin exocytosis in the differentiated state is controlled by miR‐7, miR‐375 and miR‐335. MiR‐33a and MiR‐33b play crucial roles in cholesterol and lipid metabolism, whereas miR‐103 and miR‐107 regulates hepatic insulin sensitivity. In muscle tissue, a defined number of mi RNAs (miR‐1, miR‐133, miR‐206) control myofibre type switch and induce myogenic differentiation programmes. Similarly, in adipose tissue, a defined number of mi RNAs control white to brown adipocyte conversion or differentiation (miR‐365, miR‐133, miR‐455). The discovery of circulating mi RNAs in exosomes emphasizes their importance as both endocrine signalling molecules and potentially disease markers. Their dysregulation in metabolic diseases, such as obesity, type 2 diabetes and atherosclerosis stresses their potential as therapeutic targets. This review emphasizes current ideas and controversies within mi RNA research in metabolism.

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          Adipocytes as regulators of energy balance and glucose homeostasis.

          Adipocytes have been studied with increasing intensity as a result of the emergence of obesity as a serious public health problem and the realization that adipose tissue serves as an integrator of various physiological pathways. In particular, their role in calorie storage makes adipocytes well suited to the regulation of energy balance. Adipose tissue also serves as a crucial integrator of glucose homeostasis. Knowledge of adipocyte biology is therefore crucial for understanding the pathophysiological basis of obesity and metabolic diseases such as type 2 diabetes. Furthermore, the rational manipulation of adipose physiology is a promising avenue for therapy of these conditions.
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            MiR-33 contributes to the regulation of cholesterol homeostasis.

            Cholesterol metabolism is tightly regulated at the cellular level. Here we show that miR-33, an intronic microRNA (miRNA) located within the gene encoding sterol-regulatory element-binding factor-2 (SREBF-2), a transcriptional regulator of cholesterol synthesis, modulates the expression of genes involved in cellular cholesterol transport. In mouse and human cells, miR-33 inhibits the expression of the adenosine triphosphate-binding cassette (ABC) transporter, ABCA1, thereby attenuating cholesterol efflux to apolipoprotein A1. In mouse macrophages, miR-33 also targets ABCG1, reducing cholesterol efflux to nascent high-density lipoprotein (HDL). Lentiviral delivery of miR-33 to mice represses ABCA1 expression in the liver, reducing circulating HDL levels. Conversely, silencing of miR-33 in vivo increases hepatic expression of ABCA1 and plasma HDL levels. Thus, miR-33 appears to regulate both HDL biogenesis in the liver and cellular cholesterol efflux.
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              MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis.

              Proper coordination of cholesterol biosynthesis and trafficking is essential to human health. The sterol regulatory element-binding proteins (SREBPs) are key transcription regulators of genes involved in cholesterol biosynthesis and uptake. We show here that microRNAs (miR-33a/b) embedded within introns of the SREBP genes target the adenosine triphosphate-binding cassette transporter A1 (ABCA1), an important regulator of high-density lipoprotein (HDL) synthesis and reverse cholesterol transport, for posttranscriptional repression. Antisense inhibition of miR-33 in mouse and human cell lines causes up-regulation of ABCA1 expression and increased cholesterol efflux, and injection of mice on a western-type diet with locked nucleic acid-antisense oligonucleotides results in elevated plasma HDL. Our findings indicate that miR-33 acts in concert with the SREBP host genes to control cholesterol homeostasis and suggest that miR-33 may represent a therapeutic target for ameliorating cardiometabolic diseases.
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                Author and article information

                Contributors
                ltd@ruc.dk
                Journal
                Acta Physiol (Oxf)
                Acta Physiol (Oxf)
                10.1111/(ISSN)1748-1716
                APHA
                Acta Physiologica (Oxford, England)
                John Wiley and Sons Inc. (Hoboken )
                1748-1708
                1748-1716
                05 April 2016
                February 2017
                : 219
                : 2 ( doiID: 10.1111/apha.2017.219.issue-2 )
                : 346-361
                Affiliations
                [ 1 ] Center for Basic Metabolic Research Faculty of HealthUniversity of Copenhagen CopenhagenDenmark
                [ 2 ] Department of Science and EnvironmentRoskilde University RoskildeDenmark
                Author notes
                [*] [* ] Correspondence: L. T. Dalgaard, PhD, Associate Professor, Department of Science and Environment, Roskilde University, Universitetsvej 1, Bldg. 28A1, DK‐4000 Roskilde, Denmark.

                E‐mail: ltd@ 123456ruc.dk

                Author information
                http://orcid.org/0000-0002-3598-2775
                Article
                APHA12681
                10.1111/apha.12681
                5297868
                27009502
                42204d6b-f84e-4f68-8efa-c1a9c0f1fa32
                © 2016 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 11 January 2016
                : 06 February 2016
                : 11 March 2016
                : 21 March 2016
                Page count
                Figures: 2, Tables: 1, Pages: 16, Words: 11977
                Funding
                Funded by: Novo Nordisk Foundation
                Funded by: Roskilde University
                Funded by: Danish Medical Research Council
                Award ID: 1331‐00033
                Categories
                Review
                Reviews
                Custom metadata
                2.0
                apha12681
                February 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.0.5 mode:remove_FC converted:08.02.2017

                Anatomy & Physiology
                adipocytes,metabolism,microrna,non‐alcoholic hepato‐steatosis,type 2 diabetes mellitus,β‐cells

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