NHP Liver treated with Vehicle or LXR Ligand

The LXR-regulated E3 ubiquitin ligase IDOL controls LDLR receptor stability independent of SREBP and PCSK9, but its relevance to plasma lipid levels is unknown. Here we demonstrate that the effects of the LXRIDOL axis are both tissue- and species-specific. In mice, LXR agonist induces Idol expression in peripheral tissues but not in liver, and does not change plasma LDL levels. Accordingly, Idol-deficient mice exhibit elevated LDLR protein levels in peripheral tissues but not in the liver and have minimal change in plasma LDL levels. By contrast, LXR activation in cynomolgus monkeys induces hepatic IDOL expression, reduces LDLR protein, and raises plasma LDL levels. Knockdown of IDOL in monkeys with an antisense oligonucleotide blunts the effect of LXR agonist on LDL levels. These results implicate IDOL as a modulator of plasma lipid levels in primates and support further investigation into IDOL inhibition as a strategy for LDL lowering in humans.

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Hong C, Marshall SM, McDaniel AL, Graham M, Layne JD, Cai L, Scotti E, Boyadjian R, Kim J, Chamberlain BT, Tangirala RK, Jung ME, Fong L, Lee R, Young SG, Temel RE, Tontonoz P