Author:
Clifford Bethan L.,Jarrett Kelsey E.,Cheng Joan,Cheng Angela,Seldin Marcus,Morand Pauline,Lee Richard,Baldan Angel,de Aguiar Vallim Thomas Q.,Tarling Elizabeth J.
Abstract
AbstractIncreasing the availability of hepatic low-density lipoprotein receptors (LDLR) remains a major clinical target for reducing circulating plasma LDL cholesterol (LDL-C) levels. Here, we identify the molecular mechanism underlying genome-wide significant associations in theGOLIATHlocus with plasma LDL-C levels. We demonstrate that GOLIATH is an E3 ubiquitin ligase that ubiquitinates the LDL Receptor resulting in redistribution away from the plasma membrane. Overexpression of GOLIATH decreases hepatic LDLR and increases plasma LDL-C levels. Silencing ofGoliathusing antisense oligonucleotides, germline deletion, or AAV-CRISPRin vivostrategies increases hepatic LDLR abundance and availability, thus decreasing plasma LDL-C.In vitroubiquitination assays demonstrate RING-dependent regulation of LDLR abundance at the plasma membrane. Our studies identify GOLIATH as a novel post-translational regulator of LDL-C levels via modulation of LDLR availability, which is likely important for understanding the complex regulation of hepatic LDLR.
Publisher
Cold Spring Harbor Laboratory
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