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

Down syndrome critical region (DSCR)-1functions 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-1expression in the liver and aortic atheroma. InDscr-1-null mice fed a high-fat diet, oxidative- and endoplasmic reticulum (ER)-stress was induced and sterol regulatory element-binding protein (SREBP) 2production 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 to ApoE deficiency alone. However, expression 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. We analyzed genome wide gene expression of liver among wild type, Dscr-1 knockout, ApoE knockout and Dscr-1; ApoE double-knockout mice with two independent experiments. Sample number was 8 samples. In these experiments, wild type was used as control. Moreover, we analyzed endothelial cells derived from aorta of Dscr-1 knockout mice or Dscr-1; ApoE double -knockout mice with two independent experiments. Sample number was four. In thees experiments, Dscr-1 was used as control.