ASGR1 refers to both a specific gene and the protein it produces. The ASGR1 gene carries instructions for building the asialoglycoprotein receptor 1 protein. This protein performs specialized tasks within the body. Understanding this relationship is foundational to its broader biological implications.
The Role of ASGR1 in the Body
The ASGR1 protein acts as a receptor on the surface of liver cells (hepatocytes). Its function is to recognize and clear specific proteins from the bloodstream. These targeted proteins, called asialoglycoproteins, are proteins with certain sugar chains removed from their surfaces.
Once an asialoglycoprotein binds to the ASGR1 receptor, the complex is internalized into the liver cell through endocytosis. This complex is then transported to a sorting compartment, where the receptor and its bound glycoprotein separate. The ASGR1 receptor is recycled back to the cell surface, while cleared glycoproteins are directed for degradation within the cell’s lysosomal centers. This continuous process helps maintain the proper balance of proteins circulating in the body.
Genetic Variations and Their Impact
The ASGR1 gene can exhibit different versions or alterations in its DNA sequence, known as genetic variants. Some of these variants can lead to a “loss-of-function” in the ASGR1 protein. This means the protein is either less efficient or produced in reduced amounts.
For example, a rare 12-base-pair deletion within intron 4 of the ASGR1 gene can activate a hidden splice site, resulting in a truncated and unstable protein. Another loss-of-function variant involves a 4-base-pair insertion that introduces an early stop signal at position 158. These genetic changes directly impair the ASGR1 protein’s ability to effectively bind and clear its target asialoglycoproteins from circulation.
Connection to Human Health and Disease
Loss-of-function variants in the ASGR1 gene impact human health, particularly cardiovascular health. Individuals carrying these variants often exhibit lower levels of non-HDL cholesterol, which includes “bad” cholesterol like LDL. For instance, heterozygous carriers of the 12-base-pair deletion variant have shown a decrease of approximately 13.6 to 15.3 mg per deciliter in non-HDL cholesterol compared to non-carriers.
This reduction in cholesterol is associated with a significantly decreased risk of coronary artery disease and heart attacks. Studies indicate that carriers of the del12 variant experience a 34% lower risk of coronary artery disease. The protective effect of these ASGR1 variants extends beyond cholesterol lowering, with additional mechanisms contributing to improved cardiovascular health. Research in animal models, such as ASGR1-deficient pigs, indicates that the cholesterol-lowering effect may involve reduced cholesterol synthesis in the liver and enhanced clearance of low-density lipoprotein (LDL).
Beyond its established link to cardiovascular health, ASGR1 is also an area of active research in other conditions. Investigation is ongoing into its potential role in non-alcoholic fatty liver disease (NAFLD), where studies in mice suggest ASGR1 deficiency might lead to increased fat accumulation in adipose tissue or be associated with liver damage during obesity. Furthermore, ASGR1 has been identified as a potential receptor that facilitates the entry of certain viruses, including SARS-CoV-2, into liver cells, offering new avenues for understanding viral infections and developing therapeutic strategies. These connections underscore the broad scientific and medical interest in ASGR1.