RNAs and RNA-Binding Proteins in Immuno-Metabolic Homeostasis and Diseases.

Esam S B Salem,Vishnupriya J Borra,Takahisa Nakamura,Andrew D Vonberg,Rupinder K Gill

doi:10.3389/fcvm.2019.00106

Abstract

The increasing prevalence of worldwide obesity has emerged as a major risk factor for type 2 diabetes (T2D), hepatosteatosis, and cardiovascular disease. Accumulating evidence indicates that obesity has strong inflammatory underpinnings tightly linked to the development of metabolic diseases. However, the molecular mechanisms by which obesity induces aberrant inflammation associated with metabolic diseases are not yet clearly defined. Recently, RNAs have emerged as important regulators of stress responses and metabolism. RNAs are subject to changes in modification status, higher-order structure, and cellular localization; all of which could affect the affinity for RNA-binding proteins (RBPs) and thereby modify the RNA-RBP networks. Proper regulation and management of RNA characteristics are fundamental to cellular and organismal homeostasis, as well as paramount to health. Identification of multiple single nucleotide polymorphisms (SNPs) within loci of fat mass- and obesity-associated protein (FTO) gene, an RNA demethylase, through genome-wide association studies (GWAS) of T2D, and functional assessments of FTO in mice, support the concept that disruption in RNA modifications leads to the development of human diseases including obesity and metabolic disorder. In obesity, dynamic alterations in modification and localization of RNAs appear to modulate the RNA-RBP networks and activate proinflammatory RBPs, such as double-stranded RNA (dsRNA)-dependent protein kinase (PKR), Toll-like receptor (TLR) 3 and TLR7, and RNA silencing machinery. These changes induce aberrant inflammation and the development of metabolic diseases. This review will describe the current understanding of the underlying causes of these common and altered characteristics of RNA-RBP networks which will pave the way for developing novel approaches to tackle the pandemic issue of obesity.

Highlights

In the past several decades, dramatic and rapid changes in lifestyle and dietary trends have led to obesity becoming a worldwide problem, bringing with it a host of chronic metabolic diseases, including type 2 diabetes (T2D), nonalcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), and cardiovascular disease (CVD)
While there is still controversy surrounding the role of TRBP in regulating PKR activity [168, 169], these findings suggest that, in the setting of metabolic inflammation, mitogen-activated protein kinases (MAPKs)-induced TRBP phosphorylation leads to PKR activation, followed by eIF2α phosphorylation and Jun Nterminal kinase (JNK) activation, as well as increased global miRNA expression, which are all observed simultaneously in obese liver
Hepatic Ago2-deficiency resulted in increased expression of AMPKα1 with activation of AMPK, a critical regulator of energy metabolism, reduced expression of miR-148a, and enhanced general protein translation that contributed to ATP consumption and AMPK activation [27, 179]. These findings suggest that Ago2 has the unique function of regulating energy production and consumption in the liver, and these data point to hepatic Ago2-mediated RNA silencing being a key regulator of energy metabolism under obesity-related metabolic conditions

Summary

Introduction

In the past several decades, dramatic and rapid changes in lifestyle and dietary trends have led to obesity becoming a worldwide problem, bringing with it a host of chronic metabolic diseases, including type 2 diabetes (T2D), nonalcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), and cardiovascular disease (CVD). The C-PKR KO mice on a mixed 129Sv x BALB/c background in a HFD study gained less weight and exhibited improved glucose tolerance and insulin sensitivity with decreased JNK activation and eIF2α phosphorylation within metabolic tissues as compared to wild-type control mice [20].

Results

Conclusion