Regulation of intestinal LDLR by the LXR-IDOL axis.

BACKGROUND AND AIMS: Cholesterol metabolism is tightly regulated by transcriptional and post-transcriptional mechanisms. Accordingly, dysregulation of cholesterol metabolism is a major risk factor for the development of coronary artery disease and associated complications. In recent years, it has become apparent that next to the liver, the intestine plays a key role in systemic cholesterol metabolism by governing cholesterol absorption, secretion, and incorporation into lipoprotein particles. We have previously demonstrated that the Liver X receptor (LXR)-regulated E3 ubiquitin ligase inducible degrader of LDLR (IDOL) is a regulator of cholesterol uptake owing to its ability to promote the ubiquitylation of the low-density lipoprotein receptor (LDLR). However, whether the LXR-IDOL-LDLR axis regulates the LDLR in the intestine and whether this influences intestinal cholesterol homeostasis is not known. METHODS: In this study, we evaluated the role of the LXR-IDOL-LDLR axis in enterocyte cell models and in primary enterocytes isolated from Idol(-/-) and wild type mice. Furthermore, we studied the regulation of intestinal LDLR in Idol(-/-) and in wild type mice treated with the LXR agonist GW3965. Finally, we assessed ezetimibe-induced trans-intestinal cholesterol efflux in Idol(-/-) mice. RESULTS: We show that in a wide range of intestinal cell lines LXR activation decreases LDLR protein abundance, cell surface occupancy, and LDL uptake in an IDOL-dependent manner. Similarly, we find that pharmacological dosing of C57BL6/N mice with the LXR agonist GW3965 increases Idol expression across the intestine with a concomitant reduction in Ldlr protein. Conversely, primary enterocytes isolated from Idol(-/-) mice have elevated Ldlr. To test whether these changes contribute to trans-intestinal cholesterol efflux, we measured fecal cholesterol in mice following ezetimibe dosing, but found no differences between Idol(-/-) and control mice in this setting. CONCLUSIONS: In conclusion, our study establishes that the LXR-IDOL-LDLR axis is active in the intestine and is part of the molecular circuitry that maintains cholesterol homeostasis in enterocytes.

The E3 ubiquitin ligase inducible degrader of the LDL receptor/myosin light chain interacting protein in health and disease.

PURPOSE OF REVIEW: The RING E3 ubiquitin ligase inducible degrader of the LDL receptor (IDOL, also known as MYLIP) promotes ubiquitylation and subsequent lysosomal degradation of the LDL receptor (LDLR), thus acting to limit uptake of lipoprotein-derived cholesterol into cells. Next to the LDLR, IDOL also promotes degradation of two related receptors, the very LDL receptor (VLDLR) and apolipoprotein E receptor 2 (APOER2), which have important signaling functions in the brain. We review here the emerging role of IDOL in lipoprotein and energy metabolism, neurodegenerative diseases, and the potential for therapeutic targeting of IDOL. RECENT FINDINGS: Genetic studies suggest an association between IDOL and lipoprotein metabolism in humans. Studies in rodents and nonhuman primates support an in-vivo role for IDOL in lipoprotein metabolism, and also uncovered an unexpected role in whole-body energy metabolism. Recent evaluation of IDOL function in the brain revealed a role in memory formation and progression of Alzheimer's disease. The report of the first IDOL inhibitor may facilitate further investigations on therapeutic strategies to target IDOL. SUMMARY: IDOL is emerging as an important determinant of lipid and energy metabolism in metabolic disease as well as in Alzheimer's disease. IDOL targeting may be beneficial in treating these conditions.

Inactivation of the E3 Ubiquitin Ligase IDOL Attenuates Diet-Induced Obesity and Metabolic Dysfunction in Mice.

Objective- The E3 ubiquitin ligase IDOL (inducible degrader of the LDLR [LDL (low-density lipoprotein) receptor]) is a post-transcriptional regulator of LDLR abundance. Model systems and human genetics support a role for IDOL in regulating circulating LDL levels. Whether IDOL plays a broader metabolic role and affects development of metabolic syndrome-associated comorbidities is unknown. Approach and Results- We studied WT (wild type) and Idol(-/-) (Idol-KO) mice in 2 models: physiological aging and diet-induced obesity. In both models, deletion of Idol protected mice from metabolic dysfunction. On a Western-type diet, Idol loss resulted in decreased circulating levels of cholesterol, triglycerides, glucose, and insulin. This was accompanied by protection from weight gain in short- and long-term dietary challenges, which could be attributed to reduced hepatosteatosis and fat mass in Idol-KO mice. Although feeding and intestinal fat uptake were unchanged in Idol-KO mice, their brown adipose tissue was protected from lipid accumulation and had elevated expression of UCP1 (uncoupling protein 1) and TH (tyrosine hydroxylase). Indirect calorimetry indicated a marked increase in locomotion and suggested a trend toward increased cumulative energy expenditure and fat oxidation. An increase in in vivo clearance of reconstituted lipoprotein particles in Idol-KO mice may sustain this energetic demand. In the BXD mouse genetic reference population, hepatic Idol expression correlates with multiple metabolic parameters, thus providing support for findings in the Idol-KO mice. Conclusions- Our study uncovers an unrecognized role for Idol in regulation of whole body metabolism in physiological aging and on a Western-type diet. These findings support Idol inhibition as a therapeutic strategy to target multiple metabolic syndrome-associated comorbidities.