On August 3, Prof. Song Baoliang’s team from the College of Life Sciences at Wuhan University published a paper in Nature in which they revealed that the inhibition of the ASGR1 protein promotes cholesterol excretion to bile and feces, thereby reducing blood and liver lipid levels, with significant efficacy in atherosclerosis and fatty liver.
The paper is entitled “Inhibition of ASGR1 decreases lipid levels by promoting cholesterol excretion”, with Wang Juqiong, a postdoctoral fellow in the College of Life Sciences, Wuhan University as its first author and Song Baoliang as its corresponding author. Other co-authors from the College of Life Sciences include Li Liangliang, MSc, Hu Ao, PhD, Deng Gang, MSc, Wei Jian, PhD, Li Yunfeng, PhD, Liu Yuanbin, PhD, Qiu Zhiping, PhD, Shi Xiongjie, associate professor, Zhao Xiaolu, associate professor, and Luo Jie, professor. Wuhan University is the sole authorship unit.
High cholesterol is a major risk factor for cardiovascular disease (Chen et al., 2019; Luo et al., 2020), and decreasing lipid levels is essential for the prevention and treatment of cardiovascular diseases. Although existing lipid-lowering drugs such as statins, ezetimibe and PCSK9 inhibitors can decrease lipid levels to different degrees, they have certain side effects and limitations (Luo et al., 2022). For example, statins and PCSK9 inhibitors cause cholesterol in the blood to enter the liver, altering cholesterol distribution and risking an increased burden on the liver whereas ezetimibe inhibits cholesterol absorption but has a limited lipid-lowering effect. Due to the cyclopentane polyhydrophenanthrene structure of cholesterol, it is difficult for human cells to degrade cholesterol molecules efficiently. If cholesterol can be excreted from the body, it would be an ideal strategy to decrease lipid levels.
ASGR1 is a glycoprotein receptor discovered in the 1970s that is primarily expressed on hepatocyte membranes. It binds to desialic acid glycoproteins and endocytoses and transports them to lysosomes for degradation. In 2016, a population-based genome-wide association analysis showed that mutations in the ASGR1 gene were associated with hypolipidemia, but the molecule responsible was unclear (Nioi et al., 2016). In the present work, researchers found that inhibition of ASGR1 led to increased expression of ABCG5 and ABCG8, which drains cholesterol into the bile and further removed cholesterol from the body through feces, thereby greatly reducing lipid levels in the blood and liver. Neutralizing antibodies to ASGR1 have also been developed, which can effectively promote cholesterol efflux and has good synergistic effect with statins and ezetimibe (Wang et al., 2022).
Inhibition of the ASGR1 receptor promotes cholesterol excretion
a, Protein immunoblot analysis showed increased protein mediating cholesterol efflux in the liver of ASGR1 knockout mice. b, Serum cholesterol and triglyceride levels were significantly reduced in ASGR1 knockout mice. c, Bile was turbid in ASGR1 knockout mice, suggesting increased cholesterol in bile. d, Hepatic lipids were reduced in ASGR1 knockout mice. e, Reduced ASGR1 prevented atherosclerotic plaque formation. f, Brief description of ASGR1 action pattern.
Many diseases, such as cardiovascular diseases, fatty liver and neurodegenerative diseases, are closely related to the accumulation of cholesterol. This research has laid an important foundation for the development of lipid-lowering drugs that promote cholesterol excretion, with potentially great economic and social benefits.
Song Baoliang’s team
The research was funded by the National Natural Science Foundation of China, the Key R&D Program of the Ministry of Science and Technology, Wuhan University, and the Tencent Xplore Prize.
Link to the paper：https://www.nature.com/articles/s41586-022-05006-3
Rewritten by Zhang Yuhua
Edited by: Wang Xuanqi, Sylvia, Xi Bingqing
