Regulation of intestinal LDLR by the LXR-IDOL axis
| Autor: | Jessica K. Nelson, Nienke M. van Loon, Noam Zelcer, Martina Moeton, Suzanne A.E. van Wouw, Roelof Ottenhoff, Saskia Scheij, Jenina Kingma |
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| Přispěvatelé: | Medical Biochemistry, ACS - Atherosclerosis & ischemic syndromes, ACS - Diabetes & metabolism, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, ACS - Amsterdam Cardiovascular Sciences |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Enterocyte Ubiquitin-Protein Ligases 030204 cardiovascular system & hematology 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Ezetimibe Internal medicine medicine Animals Cholesterol metabolism TICE Liver X receptor Receptor Liver X Receptors biology Chemistry Cholesterol Ubiquitination food and beverages Orphan Nuclear Receptors Ubiquitin ligase Intestines 030104 developmental biology Endocrinology medicine.anatomical_structure LDLR Receptors LDL IDOL LDL receptor biology.protein lipids (amino acids peptides and proteins) LXR Cardiology and Cardiovascular Medicine Lipoprotein medicine.drug |
| Zdroj: | Atherosclerosis, 315, 1-9. Elsevier Ireland Ltd |
| ISSN: | 0021-9150 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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