The LXR–Idol Axis Differentially Regulates Plasma LDL Levels in Primates and Mice

Hong, Cynthia; Marshall, Stephanie M.; McDaniel, Allison L.; Graham, Mark; Layne, Joseph D.; Cai, Lei; Scotti, Eleonora; Boyadjian, Rima; Kim, Jason; Chamberlain, Brian T.; Tangirala, Rajendra K.; Jung, Michael E.; Fong, Loren G.; Lee, Richard; Young, Stephen G.; Temel, Ryan E.; Tontonoz, Peter

doi:10.1016/j.cmet.2014.10.001

Cited by 76 publications

(91 citation statements)

References 30 publications

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“…Increased IDOL-mediated degradation of the LDLR also likely explains why secreted PCSK9 accumulates in MARCH6-silenced cells; decreased LDLR prevents clearance of PCSK9 via the LDLR pathway, as also suggested previously (41). Hepatic regulation of IDOL transcription by LXRs displays a species-specific divergence (42). In human and primate hepatocytes, IDOL is robustly regulated by LXR activation, yet this does not occur in rodent hepatocytes for reasons presently unclear.…”

Section: Discussionmentioning

confidence: 76%

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

Loregger

Cook

Nelson

et al. 2016

Molecular and Cellular Biology

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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. Cholesterol is an essential constituent of cellular membranes and signaling pathways and is a precursor of sterol-derived molecules (1). Yet elevated levels of cholesterol are toxic to cells, and dysregulated cholesterol metabolism is associated, most evidently, with development of cardiovascular disease. As such, multiple transcriptional networks and posttranscriptional processes regulate the synthesis, uptake, and efflux of cholesterol. Transcriptionally, these processes are largely governed by the opposing actions of the transcription factors sterol regulatory element binding proteins (SREBPs) and the liver X receptors (LXRs) (2-6). Upon sensing low cholesterol levels in the endoplasmic reticulum (ER), SREBPs are processed into their mature, transcriptionally active form. This results in induction of the full set of genes required for de novo biosynthesis of cholesterol via the mevalonate pathway and of the low-density lipoprotein receptor (LDLR) that is required for uptake of LDL-derived cholesterol (7, 8). In contrast, LXRs, members of the nuclear receptor family, are activated when cellular cholesterol levels are elevated. Once activated by their cognate oxysterol ligands, LXRs induce cholesterol efflux pathways (e.g., via the transporters ABCA1 and ABCG1) and limit LDL uptake by inducing expression of the E3 ubiquitin ligase (E3)-inducible degrader of the LDLR (IDOL) (6, 9, 10). The coordinated action of these two transcription factor families ensures that cellular cholesterol is adequately maintained at an appropriate level.Next to transcriptional regulation, posttranscriptional mechanisms are ...

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Section: Discussionmentioning

confidence: 76%

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

Loregger

Cook

Nelson

et al. 2016

Molecular and Cellular Biology

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“…We speculate that the functional interaction between USP2 and IDOL, and the formation of a tri-partite complex with the LDLR, may be sensitive to post-transcriptional modifications, nutritional cues, or to the dynamic levels of these proteins. However, a serious limitation in experimentally testing the physiological role of the USP2-IDOL nexus is the species-dependent differences in hepatic IDOL activity and transcriptional regulation 12 ; whereas in human and in nonhuman primates, the IDOL pathway is highly active in hepatocytes and subject to strong sterol-dependent transcriptional regulation, in rodent hepatocytes it is not. Accordingly, Idol (−/−) mice do not display a marked cholesterol phenotype or changes in hepatic LDLR content.…”

Section: Discussionmentioning

confidence: 99%

“…11 Consistent with this, silencing of IDOL in nonhuman primates using an RNAi-based approach resulted in a reduction of circulating levels of LDLcholesterol, which was associated with increased levels of hepatic LDLR protein. 12 Thus, the LXR-IDOL-LDLR axis is a potent ubiquitylation-dependent mechanism to acutely limit lipoprotein-derived cholesterol uptake. 13,14 Similar to other post-translational modifications, ubiquitylation is reversible; a process dependent on the activity of deubiquitylases.…”

mentioning

confidence: 99%

The Deubiquitylase USP2 Regulates the LDLR Pathway by Counteracting the E3-Ubiquitin Ligase IDOL

Nelson

Sorrentino

Trezza

et al. 2016

Circulation Research

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Rationale: The low-density lipoprotein (LDL) receptor (LDLR) is a central determinant of circulating LDL-cholesterol and as such subject to tight regulation. Recent studies and genetic evidence implicate the inducible degrader of the LDLR (IDOL) as a regulator of LDLR abundance and of circulating levels of LDL-cholesterol in humans. Acting as an E3-ubiquitin ligase, IDOL promotes ubiquitylation and subsequent lysosomal degradation of the LDLR. Consequently, inhibition of IDOL-mediated degradation of the LDLR represents a potential strategy to increase hepatic LDL-cholesterol clearance. Objective: To establish whether deubiquitylases counteract IDOL-mediated ubiquitylation and degradation of the LDLR. Methods and Results: Using a genetic screening approach, we identify the ubiquitin-specific protease 2 (USP2) as a post-transcriptional regulator of IDOL-mediated LDLR degradation. We demonstrate that both USP2 isoforms, USP2-69 and USP2-45, interact with IDOL and promote its deubiquitylation. IDOL deubiquitylation requires USP2 enzymatic activity and leads to a marked stabilization of IDOL protein. Paradoxically, this also markedly attenuates IDOL-mediated degradation of the LDLR and the ability of IDOL to limit LDL uptake into cells. Conversely, loss of USP2 reduces LDLR protein in an IDOL-dependent manner and limits LDL uptake. We identify a tri-partite complex encompassing IDOL, USP2, and LDLR and demonstrate that in this context USP2 promotes deubiquitylation of the LDLR and prevents its degradation. Conclusions: Our findings identify USP2 as a novel regulator of lipoprotein clearance owing to its ability to control ubiquitylation-dependent degradation of the LDLR by IDOL.

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“…(I) Transcriptional regulation of IDOL and its activity shows strong, species-dependent differences, as also pointed out by the authors (18). For example, in primates the LXR-IDOL-LDLR axis strongly regulates hepatic lipoprotein metabolism, while this is not the case in mice.…”

Section: The Lxr-idol-ldlr Axis In Admentioning

confidence: 65%

Idolizing the clearance of Amyloid-β by microglia

Loon

Zelcer

2016

Ann. Transl. Med.

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The LXR–Idol Axis Differentially Regulates Plasma LDL Levels in Primates and Mice

Cited by 76 publications

References 30 publications

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

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

The Deubiquitylase USP2 Regulates the LDLR Pathway by Counteracting the E3-Ubiquitin Ligase IDOL

Idolizing the clearance of Amyloid-β by microglia

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