Roles of microRNAs in carbohydrate and lipid metabolism disorders and their therapeutic potential

Highlights

• MiRNAs regulate multiple stages of carbohydrate and lipid metabolism in humans.

• Dysregulation of metabolism-related miRNAs triggers the development of metabolic disorders.

• MiRNAs own a noteworthy therapeutic potential for metabolic disorders.

Abstract

MicroRNAs (miRNAs) are small (∼21 nucleotides), endogenous, non-coding RNA molecules implicated in the post-transcriptional gene regulation performed through target mRNA cleavage or translational inhibition. In recent years, several investigations have demonstrated that miRNAs are involved in regulating both carbohydrate and lipid homeostasis in humans and other organisms. Moreover, it has been observed that the dysregulation of these metabolism-related miRNAs leads to the development of several metabolic disorders, such as type 2 diabetes, obesity, nonalcoholic fatty liver, insulin resistance, and hyperlipidemia. Hence, in this current review, with the aim to impulse the research arena of the micro-transcriptome implications in vital metabolic pathways as well as to highlight the remarkable potential of miRNAs as therapeutic targets for metabolic disorders in humans, we provide an overview of the regulatory roles of metabolism-associated miRNAs in humans and murine models.

Introduction

Both carbohydrate and lipid metabolism are vital processes of utmost importance for the growth and development of several organisms. For instance, since carbohydrates represent the principal source of energy for the central nervous system, brain, and red blood cells [1], the regulation of its metabolism within cells is fundamental for the homeostasis of the organisms. Likewise, fatty acids are the most significant energy source for humans. The most common sterol found in the cell membrane of mammals is cholesterol, and its synthesis takes place within the endoplasmic reticulum [[2], [3], [4]]. Consequently, the dysregulation of both carbohydrate and lipid metabolism could lead to severe health issues, such as cardiovascular diseases, type 2 diabetes (T2D), obesity, nonalcoholic fatty liver disease (NAFLD), atherosclerosis, hyperlipidemia, dyslipidemia, and even cancer [[5], [6], [7], [8], [9]]. In addition, the metabolic pathways of certain carbohydrates and lipids are interconnected, such as de novo lipogenesis, where glucose can be converted into fatty acids [10,11]. Hence, the study of the relationships between these mechanisms has led to a better understanding of the factors that trigger the aforementioned diseases; nevertheless, further studies are required to elucidate how intracellular and extracellular interactions occur among these processes [2,12].

MicroRNAs (miRNAs) are short (∼21 nucleotides), non-coding RNA molecules that own a fundamental role in the post-transcriptional regulation of gene expression in eukaryotes [[13], [14], [15], [16], [17]]. In the year of 1993, these molecules were first described in the nematode Caenorhabditis elegans, which led to the identification of several other miRNAs in a wide variety of organisms, including Drosophila, mice, and humans [18,19]. The central miRNA biogenesis pathway in animals is the canonical pathway, which starts with the processing of RNA polymerase II or III transcripts [20]. Primary miRNAs (pri-miRNAs) are transcribed from their respective genes and later processed into precursor miRNAs (pre-miRNAs) by the protein DiGeorge Syndrome Critical Region 8 (DGCR8) and Drosha, a ribonuclease III enzyme. The mechanism begins when DGCR8 recognizes the N6-methyl adenylated GGAC among other motifs inside the pri-miRNA duplex structure; meanwhile, Drosha cleaves the structure, results in the formation of a two nucleotide 3’ overhang on pre-miRNA [21,22]. Then, the exportin 5 (XPO5)/RanGTP complex exports pre-miRNAs to the cytoplasm. Subsequently, they are processed by the RNase III endonuclease Dicer, TAR RNA binding (TRB), and Paz proteins; this processing consists of the removal of their terminal loop, giving rise to a mature miRNA duplex. Finally, the AGO protein selects one strand of the mature miRNA to give rise to the RNA-induced silencing complex (RISC), which guides the miRNA to its corresponding mRNA target to hinder gene regulation by means of translational repression or mRNA degradation, whereas the passenger strand of the miRNA duplex is degraded [[23], [24], [25]] (Fig. 1).

Dysregulation of miRNA genes has dramatic pleiotropic effects; for example, Dicer1 knockdown has elicited systematic impairment of energy metabolism through defects of formation of pancreatic endocrine and exocrine structures, early hepatocyte apoptosis, steatosis, hypoglycemia, inhibiting the differentiation of adipocytes and inducing the death of muscle tissue [26]. Nevertheless, the list of genes regulated by a single miRNA can be very ample, while a single transcript may be targeted by more than one miRNA, making it challenging to address the proper inspection of direct interactions and specific processes in which they are involved [27]. Interestingly, several investigations have shown that miRNAs are able to regulate different phases of both the carbohydrate and lipid metabolic pathways, especially those on which key rate-limiting enzymes are implicated (Fig. 2); therefore, the aberrant expression of these RNA molecules can lead to the development of several metabolic disorders, including cancer [28,29]. For instance, miR-33, miR-122, miR-148, miR-143, and miR-26a, to name a few, are implicated in fatty acid biosynthesis, fatty acid oxidation, cholesterol metabolism, glucose metabolism, and insulin resistance [[30], [31], [32]]. Therefore, in this current review, we present some of the recent findings regarding the regulatory functions of miRNAs in the metabolism of lipids and carbohydrate in humans and murine models to have a better understanding of the roles of these RNA molecules in vital processes and to shed light on their importance as potential targets to develop therapeutic strategies towards the alleviation of metabolic diseases. In addition, we address a general inspection of the functional implications of mitochondrial miRNAs within metabolic disorders.