Elsevier

Drug Discovery Today

Volume 27, Issue 8, August 2022, Pages 2170-2180
Drug Discovery Today

Keynote (green)
Key regulatory miRNAs in lipid homeostasis: Implications for cardiometabolic diseases and development of novel therapeutics

https://doi.org/10.1016/j.drudis.2022.05.003Get rights and content

Highlights

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    Dysregulation of lipid metabolism is associated with cardiometabolic diseases.

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    microRNAs have emerged as crucial regulators of lipid metabolism.

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    We highlight key regulatory microRNAs in lipid homeostasis.

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    Several microRNAs emerge as attractive candidates for cardiometabolic therapeutics.

Abstract

Dysregulation of lipid metabolism is associated with cardiovascular/metabolic diseases, including atherosclerosis, liver diseases and type 2 diabetes mellitus (T2DM). Several miRNAs have been reported as regulators of different stages of lipid homeostasis, including cholesterol/fatty acid biosynthesis, degradation, transport, storage, and low-density (LDL) and high-density lipoprotein (HDL) formation. Indeed, various miRNAs are emerging as attractive therapeutic candidates for metabolic/cardiovascular disease (CVD). Here, we summarize the roles of miR-19b, miR-20a, miR-21, miR-27, miR-29, miR-34a, miR-144, miR-148a, and miR-199a in post-transcriptional regulation of genes involved in lipid homeostasis and their therapeutic potential. We also discuss experimental strategies for further development of these miRNAs as novel cardiometabolic therapeutics.

Introduction

miRNAs are small (∼22 nucleotides long) noncoding regulatory RNAs that serve as crucial regulators of gene expression, affecting a multitude of biological processes, including cell proliferation, differentiation, survival, and motility. Recent research has demonstrated the crucial role of miRNAs in cardiovascular physiology and pathophysiology.1 Generally, miRNAs exert their action by either translational inhibition or mRNA degradation.2 A growing body of evidence highlights the potential role of miRNAs as therapeutic agents in several physiological and pathophysiological processes, including lipid metabolism and related disorders such as dyslipidemia, obesity, hypercholesterolemia, atherosclerosis, nonalcoholic fatty liver disease (NAFLD), liver steatosis, metabolic syndrome, T2DM, and CVDs.3., 4., 5., 6. The biogenesis, mechanisms of action of miRNAs, and potential applications of miRNA mimics and anti-miR oligonucleotides have been reviewed in detail elsewhere.6., 7. These tiny RNA molecules have garnered considerable attention over the past decade owing to the ability of a single miRNA to target multiple genes in the same or different metabolic pathway.8 Importantly, miRNAs are often completely conserved across several mammalian species and, hence, could serve as therapeutic targets in preclinical and clinical trials. There have been significant recent advances in miRNA biology and technologies to deliver RNA molecules progressing miRNA therapeutics from the bench to the bedside. miRNAs have also been detected in body fluids, such as blood, saliva, and urine, as a result of cellular damage or secretion.9 These circulating miRNAs are also emerging as potential biomarkers for several CVD states.10

Section snippets

Overview of cholesterol homeostasis

Cholesterol, a precursor of several hormones and bile salts (BS) that regulate important physiological functions, is crucial for cell membrane structure and function. Therefore, regulation of cholesterol homeostasis is of vital significance. The liver is the primary site for the maintenance of cholesterol homeostasis because it is involved in the synthesis of cholesterol, synthesis/secretion of HDL particles, clearance of LDL particles and chylomicrons, and secretion of cholesterol and BS into

Post-transcriptional regulation of genes involved in cholesterol homeostasis

Several miRNAs have been reported to have important roles in post-transcriptional regulation of the above-mentioned and additional genes in cholesterol homeostasis pathways (Table 1). Among those miRNAs, miR-19b, miR-20a, miR-21, miR-27, miR-29, miR-34a, miR-144, miR-148a, and miR-199a are emerging as attractive therapeutic candidates for cardiovascular and metabolic disorders. Here, we summarize the available evidence that suggests the crucial role of these miRNAs in the regulation of genes

Development of miRNA-based therapeutics

Although numerous miRNAs are reported to have important roles in lipid homeostasis and cardiometabolic disease states (Table 1), the above-described miRNAs might serve as promising candidates for therapeutic intervention. miRNA-based therapeutics rely on modulation of miRNA activity in vivo for the treatment and clinical management of human diseases. Owing to their short sequence and conservation across most vertebrates, miRNAs are easy therapeutic targets and the same miRNA-modulating compound

Concluding remarks

Advances in bioinformatics tools and next-generation sequencing technologies in recent years have accelerated the discovery of novel miRNAs in cardiovascular pathophysiology. Additionally, preclinical studies involving large animal models have been gaining attention owing to the similarities in their cardiovascular physiology with humans and high clinical relevance. However, gaps remain in the responses observed between animals and humans in terms of drug safety and efficacy, probably because

Acknowledgements

The authors are thankful to the researchers who contributed to studies on miRNAs involved in cholesterol homeostasis. This work was supported, in part, by a grant from the Council of Scientific and Industrial Research (CSIR), Government of India to N.R.M. project number: 37(1564)/12-EMR-II.. A.A.K. and V.G. received research fellowships from the Ministry of Human Resource Development, Government of India.

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    Dr Vinayak Gupta (1986–2021) passed away due to COVID-19. He wrote an earlier version of the manuscript. A.A.K. and N.R.M. dedicate this paper to his memory.

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