RT Journal Article
SR Electronic
T1 GOLIATH regulates LDLR availability and plasma LDL cholesterol levels
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.12.09.415323
DO 10.1101/2020.12.09.415323
A1 Bethan L. Clifford
A1 Kelsey E. Jarrett
A1 Joan Cheng
A1 Angela Cheng
A1 Marcus Seldin
A1 Pauline Morand
A1 Richard Lee
A1 Angel Baldan
A1 Thomas Q. de Aguiar Vallim
A1 Elizabeth J. Tarling
YR 2020
UL http://biorxiv.org/content/early/2020/12/10/2020.12.09.415323.abstract
AB Increasing 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 the GOLIATH locus 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 of Goliath using antisense oligonucleotides, germline deletion, or AAV-CRISPR in vivo strategies increases hepatic LDLR abundance and availability, thus decreasing plasma LDL-C. In vitro ubiquitination 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.Competing Interest StatementThe authors have declared no competing interest.