Asialoglycoprotein receptor subunit Asgr1a loss results in attenuated cholesterol absorption in zebrafish fed a western diet.

One of the major pathways to clear glycoproteins from circulation is via the liver-specific asialoglycoprotein receptor. Loss of asialoglycoprotein receptor 1 (ASGR1), the major subunit of asialoglycoprotein receptor in humans, was found to correlate with lower levels of plasma apolipoprotein B-containing lipoproteins 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 High Density Lipoprotein, 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. Neither mutation altered larval, juvenile, or adult B-lp numbers or sizes. However, when challenged with a Western Diet, asgr1a mutant zebrafish exhibited less hepatic steatosis and lower hepatic triglyceride levels compared to control animals. Asgr1a mutant animals also exhibited increased levels of fecal cholesterol, due to attenuated post-prandial absorption and upregulation of liver proteins known to be involved in B-lp metabolism (e.g., microsomal triglyceride transfer protein, ApoA4). These data are consistent with the atheroprotective role of ASGR1 and reveal a previously unappreciated role for ASGR1 in modulating whole animal cholesterol flux.