Asialoglycoprotein Receptor 1 Gene Expression in Peripheral Blood Monocytes Associates with Serum Total Cholesterol and Low-Density Lipoprotein Cholesterol Levels
The asialoglycoprotein receptor 1 (ASGR1) is the major subunit of the asialoglycoprotein receptor (ASGR), which is predominantly expressed in liver parenchymal cells. Lower levels of ASGR1 expression have also been observed in peripheral blood monocytes. Recent genetic studies have revealed that ASGR1 haploinsufficiency, resulting from loss-of-function (LOF) variants, is strongly associated with significant reductions in serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels. These findings suggest that ASGR1 plays a crucial role in cholesterol metabolism. However, the exact function of ASGR1 remains largely unclear. This study aimed to explore the association between ASGR1 gene expression in monocytes and plasma cholesterol levels.
The study adhered to the principles of the Declaration of Helsinki and was approved by the Ethics Committee of the First People’s Hospital of Huaihua, University of South China. Written informed consent was obtained from all participants. A total of 104 patients hospitalized in the Cardiology Department of the First People’s Hospital of Huaihua between July 1 and August 31, 2017, were recruited. Whole blood samples were collected at 7 AM after an overnight fast for routine clinical tests and monocyte separation. Demographic and clinical characteristics, along with laboratory parameters, were collected from electronic medical records. The measurement of ASGR1 gene expression in monocytes followed the methods described in previous studies. Statistical analyses were performed using R and EmpowerStats software.
The mean age of the included patients was 58 years, with 34 (33%) being female. The relative expression of the ASGR1 gene ranged from 0.21 to 3.87. When patients were stratified by tertiles of ASGR1 gene expression, TC and LDL-C levels were significantly higher in the top tertile compared to the middle and bottom tertiles. No significant differences in ASGR1 gene expression were observed between subgroups stratified by age, gender, or clinical diagnoses. However, lower ASGR1 gene expression was noted in patients receiving cholesterol-lowering therapy compared to those not receiving such therapy.
Single-factor linear regression analysis showed that log-transformed ASGR1 gene expression was significantly associated with TC and LDL-C levels but not with other lipids. Multiple linear regression analysis, after adjusting for gender, clinical diagnoses, and cholesterol-lowering therapy, revealed a pronounced association between ASGR1 gene expression and TC and LDL-C levels in patients aged <60 years. Specifically, for each 1-SD increase in log-transformed ASGR1 gene expression, TC increased by 2.11 mmol/L and LDL-C increased by 1.77 mmol/L. When the bottom tertile of ASGR1 gene expression was used as a reference, TC levels increased by 0.44 and 1.10 mmol/L from the middle to the top tertile, respectively. Similarly, LDL-C levels increased in parallel with the tertiles of ASGR1 gene expression. However, this association was not significant in patients aged ≥60 years.
Multivariate smoothing spline plots, adjusted for gender, clinical diagnosis, and cholesterol-lowering therapy, demonstrated that plasma TC and LDL-C levels increased with increasing expression of log-transformed ASGR1 gene in a linear dose-response manner in patients aged <60 years but not in those aged ≥60 years.
Previous studies on ASGR1 knockout mice and humans carrying LOF variants of ASGR1 have shown significantly lower TC and LDL-C levels, indicating that ASGR1 is involved in cholesterol metabolism. While prior research has focused on hepatic ASGR1, this study highlights the role of monocyte ASGR1. The findings suggest that ASGR1 gene expression in monocytes is positively associated with plasma TC and LDL-C levels in a dose-response manner in patients aged <60 years, indicating that monocyte ASGR1 may also play a role in cholesterol metabolism. However, the physiological function of ASGR1 remains unclear.
Monocytes are the precursors of macrophages, and it is important to determine whether macrophages express functional ASGR1 to clarify its role in cholesterol metabolism. Genetic studies have shown that LOF variants of ASGR1 have a larger effect on the risk of coronary artery disease than anticipated by their effect on reduced cholesterol levels. If LOF variants result in defective functional ASGR1 in both hepatocytes and monocytes (macrophages), these phenotypes could be reasonably explained. Additionally, cholesterol-lowering drugs have been shown to suppress ASGR1 gene expression, raising the question of whether the decreased ASGR1 gene expression induced by these drugs contributes to their cholesterol-lowering effects.
While these findings provide new insights into the potential role of monocyte ASGR1 in modulating TC and LDL-C levels, much work remains to be done to determine whether ASGR1 could be a target for cholesterol-lowering therapies. Further research is needed to clarify the molecular mechanisms underlying the role of ASGR1 in cholesterol metabolism.
This work was supported by grants from the Natural Science Foundation of Hunan Province in China and the Science and Technology Plan Project of the Health Commission of Hunan Province in China. The authors have declared no conflicts of interest.
doi.org/10.1097/CM9.0000000000000862
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