Language:

Inhibition of ASGR1 decreases lipid levels by promoting cholesterol excretion

Nature (London), 2022-08, Vol.608 (7922), p.413-420 [Peer Reviewed Journal]

Copyright Nature Publishing Group Aug 11, 2022 ;ISSN: 0028-0836 ;EISSN: 1476-4687 ;DOI: 10.1038/s41586-022-05006-3

Full text available

Citations Cited by

Actions
1. Add to My Research
2. Remove from My Research
3. E-mail
4. Print
5. Permalink
6. Citation
7. EasyBib
8. EndNote
9. RefWorks
10. Delicious
11. Export RIS
12. Export BibTeX

Title:
Inhibition of ASGR1 decreases lipid levels by promoting cholesterol excretion
Author: Wang, Ju-Qiong ; Li, Liang-Liang ; Hu, Ao ; Deng, Gang ; Wei, Jian ; Li, Yun-Feng ; Liu, Yuan-Bin ; Lu, Xiao-Yi ; Qiu, Zhi-Ping ; Shi, Xiong-Jie ; Zhao, Xiaolu ; Luo, Jie ; Song, Bao-Liang
Subjects: ABCA1 protein ; Ablation ; Amino acids ; Antibodies ; Atorvastatin ; ATP-binding protein ; Bile ; Biosynthesis ; BRCA1 protein ; Cardiovascular diseases ; Cholesterol ; Degradation ; Drugs ; Endocytosis ; Excretion ; Fatty acids ; Gene expression ; Health risks ; High density lipoprotein ; Internalization ; Lipid metabolism ; Lipids ; Lipogenesis ; Lipoproteins ; Liver ; Lysosomes ; Metabolism ; Proteins ; Risk analysis ; Risk factors ; Risk management ; Risk reduction ; Rodents ; Ubiquitin
Is Part Of: Nature (London), 2022-08, Vol.608 (7922), p.413-420
Description: High cholesterol is a major risk factor for cardiovascular disease1. Currently, no drug lowers cholesterol through directly promoting cholesterol excretion. Human genetic studies have identified that the loss-of-function Asialoglycoprotein receptor 1 (ASGR1) variants associate with low cholesterol and a reduced risk of cardiovascular disease2. ASGR1 is exclusively expressed in liver and mediates internalization and lysosomal degradation of blood asialoglycoproteins3. The mechanism by which ASGR1 affects cholesterol metabolism is unknown. Here, we find that Asgrl deficiency decreases lipid levels in serum and liver by stabilizing LXRa. LXRa upregulates ABCA1 and ABCG5/G8, which promotes cholesterol transport to high-density lipoprotein and excretion to bile and faeces4, respectively. ASGR1 deficiency blocks endocytosis and lysosomal degradation ofglycoproteins, reduces amino-acid levels in lysosomes, and thereby inhibits mTORCl and activates AMPK. On one hand, AMPK increases LXRa by decreasing its ubiquitin ligases BRCA1/BARD1. On the other hand, AMPK suppresses SREBP1 that controls lipogenesis. Anti-ASGRl neutralizing antibody lowers lipid levels by increasing cholesterol excretion, and shows synergistic beneficial effects with atorvastatin or ezetimibe, two widely used hypocholesterolaemic drugs. In summary, this study demonstrates that targeting ASGR1 upregulates LXRa, ABCA1 and ABCG5/ G8, inhibits SREBP1 and lipogenesis, and therefore promotes cholesterol excretion and decreases lipid levels.
Publisher: London: Nature Publishing Group
Language: English
Identifier: ISSN: 0028-0836
EISSN: 1476-4687
DOI: 10.1038/s41586-022-05006-3
Source: ProQuest One Psychology
ProQuest Central

Back to results list

Previous Result 9 Next Go to Next page


INSPIRE LIBRARY - TON DUC THANG UNIVERSITY	(84-028) 37 755 057	Feedback
19 Nguyen Huu Tho St. Dist.7, HCM	thuvien@tdtu.edu.vn	Feedback

Inhibition of ASGR1 decreases lipid levels by promoting cholesterol excretion

Copyright Nature Publishing Group Aug 11, 2022 ;ISSN: 0028-0836 ;EISSN: 1476-4687 ;DOI: 10.1038/s41586-022-05006-3

Searching Remote Databases, Please Wait