Key result
asgr1a deficiency reduces diet-induced hepatic steatosis by attenuating post-prandial cholesterol absorption in zebrafish.
Why the study?
Does loss of asgr1a attenuate cholesterol absorption and hepatic steatosis in zebrafish fed a Western diet?
Does loss of asgr1a attenuate cholesterol absorption and hepatic steatosis in zebrafish fed a Western diet?
Loss of asgr1a in zebrafish attenuates cholesterol absorption and reduces hepatic steatosis, providing a mechanistic basis for the atheroprotective role of ASGR1 deficiency.
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 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. 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. Mttp, 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.
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Derrick et al. (2026) studied Hepatic steatosis and cholesterol metabolism. asgr1a mutation (loss of ASGR1) vs. Control animals was evaluated on Hepatic steatosis, hepatic triglyceride levels, and fecal cholesterol. Loss of asgr1a in zebrafish fed a Western diet resulted in less hepatic steatosis, lower hepatic triglycerides, and increased fecal cholesterol due to attenuated post-prandial absorption.
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