A MARCH6 and IDOL E3 Ubiquitin Ligase Circuit Uncouples Cholesterol Synthesis from Lipoprotein Uptake in Hepatocytes

Abstract

Cholesterol synthesis and lipoprotein uptake are tightly coordinated to ensure that the cellular level of cholesterol is adequately maintained. Hepatic dysregulation of these processes is associated with pathological conditions, most notably cardiovascular disease. Using a genetic approach, we have recently identified the E3 ubiquitin ligase MARCH6 as a regulator of cholesterol biosynthesis, owing to its ability to promote degradation of the rate-limiting enzymes 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGCR) and squalene epoxidase (SQLE). Here, we present evidence for MARCH6 playing a multifaceted role in the control of cholesterol homeostasis in hepatocytes. We identify MARCH6 as an endogenous inhibitor of the sterol regulatory element binding protein (SREBP) transcriptional program. Accordingly, loss of MARCH6 increases expression of SREBP-regulated genes involved in cholesterol biosynthesis and lipoprotein uptake. Unexpectedly, this is associated with a decrease in cellular lipoprotein uptake, induced by enhanced lysosomal degradation of the low-density lipoprotein receptor (LDLR). Finally, we provide evidence that induction of the E3 ubiquitin ligase IDOL represents the molecular mechanism underlying this MARCH6-induced phenotype. Our study thus highlights a MARCH6-dependent mechanism to direct cellular cholesterol accretion that relies on uncoupling of cholesterol synthesis from lipoprotein uptake.

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Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00890-15.

ACKNOWLEDGMENTS

We kindly thank Sanofi-Regeneron for providing the anti-PCSK9 fully humanized monoclonal antibody alirocumab. We thank members of the Zelcer group, Ben Distel, Eric Reits, and Irith Koster, for their comments and suggestions.

We declare that we have no conflicts of interest.

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. A.J.B. is supported by a grant from the National Health and Medical Research Council (1060515). N.Z. is an Established Investigator of the Dutch Heart Foundation and is supported by a VIDI grant (17.106.355) from the Netherlands Organization of Scientific Research and by an ERC Consolidator grant (617376) from the European Research Council.