Role of the Nuclear Receptor Corepressor 1 (NCOR1) in Atherosclerosis and Associated Immunometabolic Diseases.

Martin A Geiger,Francesco Paneni,Christian M Matter,Ana T Guillaumon,Sokrates Stein

doi:10.3389/fimmu.2020.569358

Abstract

Atherosclerotic cardiovascular disease is part of chronic immunometabolic disorders such as type 2 diabetes and nonalcoholic fatty liver disease. Their common risk factors comprise hypertension, insulin resistance, visceral obesity, and dyslipidemias, such as hypercholesterolemia and hypertriglyceridemia, which are part of the metabolic syndrome. Immunometabolic diseases include chronic pathologies that are affected by both metabolic and inflammatory triggers and mediators. Important and challenging questions in this context are to reveal how metabolic triggers and their downstream signaling affect inflammatory processes and vice-versa. Along these lines, specific nuclear receptors sense changes in lipid metabolism and in turn induce downstream inflammatory and metabolic processes. The transcriptional activity of these nuclear receptors is regulated by the nuclear receptor corepressors (NCORs), including NCOR1. In this review we describe the function of NCOR1 as a central immunometabolic regulator and focus on its role in atherosclerosis and associated immunometabolic diseases.

Highlights

Atherosclerosis is characterized by the accumulation of immune cells, cholesterol species and other lipids in the intimal space of arteries
The signaling cascades that are activated by inflammatory and metabolic triggers and/or mediators converge at key transcriptional regulators, which in turn coordinate the expression of specific target genes and atherogenic processes
Targeted deletions of nuclear receptor corepressor 1 (NCOR1) in immune cells, liver, adipose tissue, and muscle demonstrated that it affects pro- and anti-inflammatory gene signatures, mitochondrial function, lipid metabolism, insulin sensitivity, intestinal cholesterol absorption, thereby highlighting its immunometabolic functions, which will be discussed below [21, 35,36,37,38,39,40,41]

Summary

Introduction

Atherosclerosis is characterized by the accumulation of immune cells, cholesterol species and other lipids in the intimal space of arteries. The signaling cascades that are activated by inflammatory and metabolic triggers and/or mediators converge at key transcriptional regulators, which in turn coordinate the expression of specific target genes and atherogenic processes. While the role of lipid-binding nuclear receptor in metabolism is well established, studies over the last decade demonstrated that several of these nuclear receptors, including PPARg, LXRs, and LRH-1, mediate transrepression of pro-inflammatory molecules in the liver and/or immune cells, such as macrophages and T cells [20,21,22,23,24,25].

Results

Conclusion