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| Status |
Public on Apr 19, 2021 |
| Title |
Loss of Down syndrome critical region-1 leads to cholesterol metabolic dysfunction that exaggerates hypercholesterolemia in ApoE-null background |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
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.
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| Overall design |
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.
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| Contributor(s) |
Muramatsu M, Osawa T, Miyamura Y, Nakagawa S, Tanaka T, Kodama T, Aburatani H, Sakai J, Ryeom S, Minami T |
| Citation(s) |
33895138 |
| Submission date |
Apr 18, 2021 |
| Last update date |
Jul 20, 2021 |
| Contact name |
Takashi Minami |
| E-mail(s) |
t-minami@kumamoto-u.ac.jp
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| Organization name |
Kumamoto University
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| Street address |
2-2-1, Honjo
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| City |
Kumamoto |
| ZIP/Postal code |
860-0811 |
| Country |
Japan |
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| Platforms (1) |
| GPL1261 |
[Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA722746 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE172283_RAW.tar |
59.2 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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