Loss of Down syndrome critical region-1 leads to cholesterol metabolic dysfunction that exaggerates hypercholesterolemia in ApoE-null background

Masashi Muramatsu,Tsuyoshi Osawa,Yuri Miyamura,Suguru Nakagawa,Toshiya Tanaka,Tatsuhiko Kodama,Hiroyuki Aburatani,Juro Sakai,Sandra Ryeom,Takashi Minami

doi:10.1016/j.jbc.2021.100697

Abstract

Down syndrome critical region (DSCR)-1 functions as a feedback modulator for calcineurin-nuclear factor for activated T cell (NFAT) signals, which are crucial for cell proliferation and inflammation. Stable expression of DSCR-1 inhibits pathological angiogenesis and septic inflammation. DSCR-1 also plays a critical role in vascular wall remodeling associated with aneurysm development that occurs primarily in smooth muscle cells. Besides, Dscr-1 deficiency promotes the M1-to M2-like phenotypic switch in macrophages, which correlates to the reduction of denatured cholesterol uptakes. However, the distinct roles of DSCR-1 in cholesterol and lipid metabolism are not well understood. Here, we show that loss of apolipoprotein (Apo) E in mice with chronic hypercholesterolemia induced Dscr-1 expression in the liver and aortic atheroma. In Dscr-1-null mice fed a high-fat diet, oxidative- and endoplasmic reticulum (ER) stress was induced, and sterol regulatory element-binding protein (SREBP) 2 production in hepatocytes was stimulated. This exaggerated ApoE−/−-mediated nonalcoholic fatty liver disease (NAFLD) and subsequent hypercholesterolemia. Genome-wide screening revealed that loss of both ApoE and Dscr-1 resulted in the induction of immune- and leukocyte activation-related genes in the liver compared with ApoE deficiency alone. However, expressions of inflammation-activated markers and levels of monocyte adhesion were suspended upon induction of the Dscr-1 null background in the aortic endothelium. Collectively, our study shows that the combined loss of Dscr-1 and ApoE causes metabolic dysfunction in the liver but reduces atherosclerotic plaques, thereby leading to a dramatic increase in serum cholesterol and the formation of sporadic vasculopathy.

Highlights

Atherosclerosis is one of the major causes of mortality worldwide due to the severe complications associated with it, such as acute cerebral and myocardial infarctions
The Down syndrome critical region (DSCR)-1 null mutation resulted in a significant induction in both precursor and mature forms of SREBP2, resulting in more LDL receptors (LDLR) in the primary liver of the mice (Fig. 1E)
We demonstrated that mice with Dscr-1 null mutation exhibited SREBP2 hyperactivation and susceptibility to oxidative or endoplasmic reticulum (ER) stresses and eventually developed nonalcoholic fatty liver disease (NAFLD)

Summary

Introduction

Atherosclerosis is one of the major causes of mortality worldwide due to the severe complications associated with it, such as acute cerebral and myocardial infarctions. In an atherosclerotic ApoE−/− background or PCSK9 overexpression, Dscr-1 null mice revealed significant hypercholesterolemia leading to lipid accumulation in the peripheral tissues. These data suggest that defects in cholesterol transfer observed in ApoE−/− mice are due, in part, to NFAT-mediated inflammation in hepatocytes, as shown by Dscr-1 promoter activation (Fig. 1A).

Results

Conclusion