Asialogycoprotein receptor subunit ASGR1a deficiency leads to cholesterol malabsorption in zebrafish on a high-cholesterol diet

Recently, loss of asialoglycoprotein receptor 1 (ASGR1), the major subunit of ASGPR in humans, was found to correlate with lower levels of plasma apolipoprotein B-containing lipoproteins (B-lps) and a profound reduction in cardiovascular disease risk. However, the cell and molecular biology underlying this effect was unclear.

Given that rodents carry their cholesterol largely in HDL, we selected the zebrafish model to better understand the mechanism(s) of action of ASGR1. We first characterized all possible zebrafish ASGR1 orthologs to identify zebrafish ASGR1 (asgr1a) from a collection of lectin-binding proteins. We then generated two independent mutations in asgr1a using CRISPR/Cas9.