Asgr1, also known as asialoglycoprotein receptor 1 (CLEC4H1), is a C-type lectin receptor primarily expressed in hepatocytes. It is a multivalent carbohydrate-binding receptor responsible for recognizing and eliminating circulating glycoproteins with exposed galactose (Gal) or N-acetylgalactosamine (GalNAc) as terminal glycan residues [4,5]. It has been implicated in modulating lipid metabolism, and genetic studies suggest its potential role in cardiovascular disease risk [1,5,6].

In gene-knockout (KO) mouse models, Asgr1 deficiency has multiple effects. It decreases lipid levels in serum and liver by stabilizing LXRα, which then upregulates ABCA1 and ABCG5/G8, promoting cholesterol transport to high-density lipoprotein and excretion to bile and faeces [1]. Also, Asgr1 deficiency exacerbates acetaminophen-induced acute and CCl4-induced chronic liver injuries in male mice by increasing GP73-mediated hepatic endoplasmic reticulum stress [2]. In sepsis models, ASGR1-knockdown mice show suppressed monocyte-to-macrophage differentiation, alleviated liver injury, and improved survival [3]. In ApoE-/-mice, Asgr1 deficiency improves atherosclerosis but alters liver metabolism [5].

In conclusion, Asgr1 plays a crucial role in lipid metabolism and liver-related processes. KO mouse models have revealed its significance in conditions such as hypercholesterolemia, liver injury, and sepsis-induced liver injury. Understanding Asgr1's functions through these models provides potential therapeutic targets for related diseases, but also highlights the need for careful evaluation due to possible side-effects on the liver [1,2,3,5].

References:

1. Wang, Ju-Qiong, Li, Liang-Liang, Hu, Ao, Luo, Jie, Song, Bao-Liang. 2022. Inhibition of ASGR1 decreases lipid levels by promoting cholesterol excretion. In Nature, 608, 413-420. doi:10.1038/s41586-022-05006-3. https://pubmed.ncbi.nlm.nih.gov/35922515/

2. Zhang, Zhe, Leng, Xiang Kai, Zhai, Yuan Yuan, Tao, Kai Shan, Wu, Jiang Wei. 2024. Deficiency of ASGR1 promotes liver injury by increasing GP73-mediated hepatic endoplasmic reticulum stress. In Nature communications, 15, 1908. doi:10.1038/s41467-024-46135-9. https://pubmed.ncbi.nlm.nih.gov/38459023/

3. Shi, Rui, Wang, Jiangang, Zhang, Zhen, Leng, Yiping, Chen, Alex F. 2023. ASGR1 promotes liver injury in sepsis by modulating monocyte-to-macrophage differentiation via NF-κB/ATF5 pathway. In Life sciences, 315, 121339. doi:10.1016/j.lfs.2022.121339. https://pubmed.ncbi.nlm.nih.gov/36621538/

4. Hoober, J Kenneth. 2020. ASGR1 and Its Enigmatic Relative, CLEC10A. In International journal of molecular sciences, 21, . doi:10.3390/ijms21144818. https://pubmed.ncbi.nlm.nih.gov/32650396/

5. Svecla, Monika, Moregola, Annalisa, Dalt, Lorenzo Da, Bonacina, Fabrizia, Norata, Giuseppe Danilo. 2024. ASGR1 deficiency improves atherosclerosis but alters liver metabolism in ApoE-/- mice. In Cardiovascular diabetology, 23, 428. doi:10.1186/s12933-024-02507-5. https://pubmed.ncbi.nlm.nih.gov/39616371/

6. Song, Jiali, Fang, Yang, Rao, Xiuqin, Lin, Yue, Wei, Gen. 2024. Beyond conventional treatment: ASGR1 Leading the new era of hypercholesterolemia management. In Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 180, 117488. doi:10.1016/j.biopha.2024.117488. https://pubmed.ncbi.nlm.nih.gov/39316974/