Editors' ChoiceMetabolism

Monkeying Around with LDL Receptor Levels

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Science Translational Medicine  19 Nov 2014:
Vol. 6, Issue 263, pp. 263ec197
DOI: 10.1126/scitranslmed.aaa2058

Statin class cholesterol lowering drugs, which can increase hepatic expression of the LDL receptor (LDLR), have reduced cardiovascular mortality across large patient populations. Unfortunately, patients taking statins continue to suffer high residual rates of adverse cardiovascular events, highlighting an urgent need for new cholesterol modulating therapies. Recent studies have demonstrated that a protein called inducible degrader of LDLR (IDOL), which is a robust transcriptional target of the nuclear receptor Liver X Receptor (LXR), can specifically degrade LDLR protein independently of known LDLR regulators such as SREBP and PCSK9. However, the function of the endogenous LXR-IDOL axis in cholesterol homeostasis in vivo has remained poorly understood.

To begin to address this question, Hong et al. studied cholesterol homeostasis in mice with global deficiency of IDOL. Surprisingly, they found that administration of LXR agonists to mice failed to induce hepatic IDOL or alter plasma LDL and that IDOL­-deficient mice had minimal changes in hepatic LDLR protein and plasma cholesterol. As the transcriptional circuitry governing LXR-mediated activation of IDOL is very different in mouse versus human hepatocytes, the investigators reasoned that the LXR-IDOL-LDLR signaling axis might be more accurately modeled in primates. To test this directly, they treated high-fat diet–fed cynomolgus monkeys with the synthetic LXR agonist GW3965 and found robust induction of hepatic IDOL, reduction of LDLR protein, and increased plasma LDL and total cholesterol. In an elegant series of experiments, they silenced IDOL expression in live monkeys using specific antisense oligonucleotides followed by administration of GW3965. These studies revealed that IDOL inhibition blunted LXR-mediated increase in plasma cholesterol, providing evidence that the hepatic LXR-IDOL pathway indeed functions in a species-specific manner in vivo.

Future studies to determine the role of the LXR-IDOL axis in nonhepatocytes as well as the effect of IDOL inhibition in the absence of LXR activation are likely to be therapeutically informative. Synthetic LXR agonists have been shown previously to promote reverse cholesterol transport and reduce atherosclerosis in mouse models, prompting their evaluation as a therapeutic strategy in cardiometabolic disease. However, the cholesterol raising effects of LXR agonists and the involvement of IDOL seen here in primates highlight the importance of studying such translationally relevant metabolic signaling pathways in higher mammals.

C. Hong et al., The LXR-Idol axis differentially regulates plasma LDL levels in primates and mice. Cell Metab. 5, 910–18 (2014). [Abstract]

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