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MicroRNA-mediated regulation of glucose and lipid metabolism

Abstract

In animals, systemic control of metabolism is conducted by metabolic tissues and relies on the regulated circulation of a plethora of molecules, such as hormones and lipoprotein complexes. MicroRNAs (miRNAs) are a family of post-transcriptional gene repressors that are present throughout the animal kingdom and have been widely associated with the regulation of gene expression in various contexts, including virtually all aspects of systemic control of metabolism. Here we focus on glucose and lipid metabolism and review current knowledge of the role of miRNAs in their systemic regulation. We survey miRNA-mediated regulation of healthy metabolism as well as the contribution of miRNAs to metabolic dysfunction in disease, particularly diabetes, obesity and liver disease. Although most miRNAs act on the tissue they are produced in, it is now well established that miRNAs can also circulate in bodily fluids, including their intercellular transport by extracellular vesicles, and we discuss the role of such extracellular miRNAs in systemic metabolic control and as potential biomarkers of metabolic status and metabolic disease.

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Fig. 1: Insulin synthesis and secretion in the islet β-cell and its control by miRNAs.
Fig. 2: Insulin signal transduction and metabolic responses in peripheral tissues and their control by miRNAs.
Fig. 3: HDL biogenesis and control by miRNAs in hepatocytes.
Fig. 4: Control of lipid metabolism and LDL biogenesis/turnover by miRNAs.

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Acknowledgements

The authors apologize to those whose work they omitted in this Review due to space limitations. They thank the following funding agencies for support: NIH (T32GM008061 and R35GM118144), NSF (1764421) and the Simons Foundation (597491).

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The authors contributed equally to all aspects of the original manuscript, and R.W.C made all revisions to the manuscript.

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Glossary

Argonaute (Ago) family

A class of proteins conserved in eukaryotes that associate with small RNAs such as PIWI-interacting RNAs, microRNAs and siRNAs, and together the RNA–induced silencing complex acts upon DNA or RNA targets.

Seed sequence

A heptamer sequence located at nucleotides 2–7 relative to the 5′ end of a microRNA. The seed sequence is essential for binding of the microRNA in the RNA-induced silencing complex to a target mRNA, with the binding site typically located in the 3′ untranslated region.

Bilateral animals

Animals with bilateral symmetry as an embryo. Bilateral symmetry is where the body has a left side and a right side that are mirror images of one another. Animals that do not fall into this category include sponges, ctenophores, placozoans and cnidarians.

Islets of Langerhans

Regions of the pancreas that contain endocrine cells responsible for glucose homeostasis. Constituting 1–2% of the pancreas volume, there are approximately one million islets distributed throughout the pancreas in density routes.

SNARE

Eukaryotic protein family that mediates the fusion of membrane-bound vesicles with a target membrane. Target membranes can include the plasma membrane (exocytosis) and membrane-bound compartments such as the Golgi apparatus.

Insulin-like peptides

The evolutionarily ancient superfamily of peptides that include insulin, insulin-like growth factors and peptides within the invertebrates that fulfil functions homologous to those of vertebrate insulin and insulin-like growth factors.

Barbed ends of F-actin

Actin filaments have polarity, with each filament having a barbed end and a pointed end. Actin monomers are added to filaments predominantly at the barbed end, whereas release of monomers from a filament occurs predominantly at the pointed end. In the cell, filaments are continuously turned over by dynamic monomer–filament exchange.

Incretin hormone

Incretins are peptides secreted into the circulatory system by specialized enteroendocrine cells in the gut upon nutrient ingestion and absorption. They target the islets of Langerhans, where they augment the response of β-cells to glucose by secreting insulin.

Insulin resistance

A condition where cells of the liver, fat and muscle are not as responsive to insulin doses that elicit normal responses in healthy individuals. Consequently, cells do not absorb glucose from the blood as readily, and the pancreas responds by secreting even more insulin to overcome the weak response to insulin.

Lipoprotein

Lipoproteins carry cholesterol and triglycerides in the circulation, and they can both deliver and remove lipids from cells to mediate lipid homeostasis. Lipoproteins do not simply associate with lipids into small molecular complexes, but rather are found as lipoprotein particles of various sizes in the blood plasma.

PPAR transcription factors

A family of nuclear receptor proteins that control the expression of a large number of genes involved in metabolic homeostasis, lipid, glucose and energy metabolism, adipogenesis and inflammation. Endogenous ligands for peroxisome proliferator-activated receptors (PPARs) include free fatty acids, eicosanoids and vitamin B3.

Apolipoproteins

Proteins that bind to lipids and form lipoproteins, which circulate in the blood, lymph and cerebrospinal fluid. They not only function to solubilize lipids for transport but also interact with lipoprotein receptors and lipid transport proteins to facilitate lipoprotein uptake and clearance.

Antagomir

A small synthetic RNA whose purpose is to block the action of a specific microRNA in vivo. An antagomir is fully complementary to a microRNA except for a mismatch or chemical modification at the site of RNA-induced silencing complex cleavage, so as to prevent the antagomir from being cleaved. Antagomirs often have other chemical modifications to inhibit their degradation by ribonucleases.

FGF21

A member of the fibroblast growth factor family. It is secreted from liver cells into the circulatory system. It binds to a receptor on the surface of cells of the hypothalamus and regulates simple sugar intake and preference for sweet foods.

Adipokines

Also known as adipocytokines, these molecules are cytokines that are secreted by adipose tissue. Representative adipokines include leptin, IL-6 and TNF.

PKCθ

A member of the protein kinase C (PKC) family, which phosphorylate target proteins at serine and threonine residues. Kinase activation requires a second messenger, and this PKC isoform requires binding to diacylglycerol. It does not require binding to calcium, and thus it is a member of the novel subfamily of PKCs.

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Agbu, P., Carthew, R.W. MicroRNA-mediated regulation of glucose and lipid metabolism. Nat Rev Mol Cell Biol 22, 425–438 (2021). https://doi.org/10.1038/s41580-021-00354-w

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