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

J Biol Chem. Jan-Jun 2021;296:100697. doi: 10.1016/j.jbc.2021.100697. Epub 2021 Apr 23.

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.

Keywords: Down syndrome critical region (DSCR)-1; apolipoprotein (Apo)E; hypercholesterolemia; low-density lipoprotein (LDL); nonalcoholic fatty liver disease (NAFLD); nuclear factor for activated T cells (NFAT); proprotein convertase subtilisin/kexin type (PCSK)9; regulator of calcineurin (RCAN)1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoproteins E / deficiency*
  • Apolipoproteins E / genetics*
  • Calcium-Binding Proteins / deficiency*
  • Calcium-Binding Proteins / genetics
  • Cholesterol / metabolism*
  • Gene Deletion*
  • Gene Expression Regulation
  • Hepatocytes / metabolism
  • Hypercholesterolemia / genetics*
  • Hypercholesterolemia / metabolism
  • Mice
  • Muscle Proteins / deficiency*
  • Muscle Proteins / genetics
  • Phenotype

Substances

  • Apolipoproteins E
  • Calcium-Binding Proteins
  • DSCR1 protein, mouse
  • Muscle Proteins
  • Cholesterol