Loss of asgr1a leads to the secretion of excess dietary cholesterol in zebrafish

One of the major pathways to clear glycoproteins from circulation is via the liver-specific asialoglycoprotein receptor (ASGPR). Loss of asialoglycoprotein receptor 1 ( ASGR1 ), the major subunit of ASGPR, was recently found to correlate with lower levels of plasma apolipoprotein B- containing lipoproteins (B-lps) and a profoundly reduced risk of cardiovascular disease in humans. We set out to identify the zebrafish ortholog of ASGR1 ( asgr1a ) and generated two independent mutations in asgr1a using CRISPR/Cas9. Neither asgr1a mutation displayed changes in larval, juvenile, and adult B-lp numbers or sizes. However, when challenged with a Western diet, asgr1a mutant zebrafish exhibit less hepatic steatosis and lower hepatic triglyceride levels compared to control animals. Instead, the excess dietary cholesterol was excreted. While these results do not explain the cardioprotective nature of ASGR1 in humans, they indicate the importance of ASGR1 in modulating whole animal cholesterol flux.