MicroRNAs in metabolism and metabolic disorders

Abstract

MicroRNAs (miRNAs) have recently emerged as key regulators of metabolism. For example, miR-33a and miR-33b have a crucial role in controlling cholesterol and lipid metabolism in concert with their host genes, the sterol-regulatory element-binding protein (SREBP) transcription factors. Other metabolic miRNAs, such as miR-103 and miR-107, regulate insulin and glucose homeostasis, whereas miRNAs such as miR-34a are emerging as key regulators of hepatic lipid homeostasis. The discovery of circulating miRNAs has highlighted their potential as both endocrine signalling molecules and disease markers. Dysregulation of miRNAs may contribute to metabolic abnormalities, suggesting that miRNAs may potentially serve as therapeutic targets for ameliorating cardiometabolic disorders.

Figure 1. Model of the SREBP and miR-33 circuit

The sterol regulatory element-binding protein (SREBP) transcription factors act coordinately with their intronic miRNAs miR-33a and b to regulate fatty acid, triglyceride, and cholesterol homeostasis. Transcription of the SREBF1 and SREBF2 loci gives rise to the SREBP-1 and SREBP-2 transcription factors and the miR-33a/b miRNAs. SREBP-1 activates genes involved in fatty acid, phospholipid and triglyceride synthesis (e.g., FASN (fatty acid synthase), SCD (stearoyl-CoA desaturase) and ACC (Acetyl-CoA carboxylase)) whereas SREBP-2 activates genes involved in cholesterol synthesis/uptake, such as HMGCR (3-hydroxy-3-methylglutarylcoenzyme A reductase) and LDLR (Low-Density Lipoprotein Receptor). miR-33a and b act to repress genes functioning in fatty acid β-oxidation (e.g., CROT (carnitine O-octanoyltransferase), HADHB (hydroxyacyl– coenzyme A dehydrogenase/3-ketoacyl–coenzyme A thiolase/enoyl–coenzyme A hydratase [trifunctional protein], β subunit) and CPT1A (carnitine palmitoyltransferase 1A)), cholesterol efflux (e.g., ATP-binding cassette, subfamily A member 1 (ABCA1)), as well as negative regulators of SREBPs (e.g., IRS-2 (insulin receptor substrate 2), AMPKα1 (AMP-activated protein kinase α1 subunit) and SIRT6 (sirtuin 6)).

Figure 2. MiRNA regulation of insulin signalling and glucose homeostasis

Normally, upon feeding, insulin is produced in the pancreatic β-cells and upon release will reach target tissues such as the muscle, liver and adipose to cause uptake of glucose, reduce the production of glucose and to activate fat production and storage. MiRNAs have been identified that affect diverse parts of insulin signalling in pancreas, liver, muscle and adipose tissue. miR-124a and miR-34a are involved in pancreatic development (through effects on Foxo2, Rhab27a, VAMP2, and Bcl2), whereas miR-29, miR-9 and miR-375 are involved in insulin secretion (through Mct1, Onecut2, Sirt1, PDK1, and Mtpn). miR-33, miR-34a, miR-29 and miR-143 act in the liver on targets involved in insulin signalling and its regulation (such as IRS-2, SIRT6, AMPKa1, SIRT1, PIK3R1 and ORP8). miR-103 and miR-107 and miR-29 act to modulate insulin signalling in adipose tissue (through CAV-1 and Insig1, respectively). miR-29, let-7 and miR-223 act in the muscle on insulin uptake (Glut4) and insulin signalling (Igf1R, Insr and Irs2). Known and predicted targets that lack in vivo evidence are marked with a question mark. In disease conditions such as impaired insulin secretion or insulin resistance, several miRNAs are upregulated (marked with arrow).

Figure 3. The regulatory loop of miR-34a, SIRT1, FXR and p53

miR-34a is highly expressed in patients with NAFLD and NASH and type 2 diabetes. On the molecular level, miR-34a has been shown to exert its function through its effect on SIRT1. miR-34a is then in turn inhibited by SIRT1 in a regulatory loop that includes miR-34a, SIRT1, FXR and p53 to affect cholesterol, lipid and energy homeostasis as well as inflammation. A. miR-34a inhibits SIRT1 and reduces its protein level and prevents its activation of PGC-1α, PPARα and LXR (key regulators of cholesterol/lipid/energy homeostasis), and inhibition of SREBP and NF-κB (activators of lipogenesis and cholesterogenesis, and inflammation, respectively). B. SIRT1 feedback inhibits miR-34a in several ways: it deacetylates p53 and inhibits p53-dependent transcriptional activation of miR-34a. In addition, SIRT1 inhibits the miR-34a promoter through histone deacetylation. Finally, SIRT1 deacetylates and activates FXR. FXR transcriptionally activates SHP, which sequesters p53 and thus inhibits miR-34a transcription.

Figure 4. Model for the function of circulating miRNAs associated with HDL

MiRNAs such as miR-375 and miR-223 are produced in peripheral tissues and incorporated in exosomes through a mechanism controlled by nSMase2, the rate limiting enzyme in ceramide biosynthesis, and transported in the blood. Some miRNAs are also bound to high-density lipoproteins (HDL), incorporation of microRNAs into HDL is controlled by the cholesterol transporter ABCA and by nSMase. Uptake of RNA and miRNAs from exosomes in target cells does not require binding to a specific receptor. MiRNAs associated with HDL are thought to be trafficked to the liver through the reverse cholesterol transport (RCT) pathway and taken up by a scavenger receptor B I-dependent mechanism. Once inside target cells, miRNAs can then exert inhibitory effects on a range of target genes.