Foiling IDOL to Help Control Cholesterol
| Autor: | Andrew J. Brown, Joanne Hsieh |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Physiology Ubiquitin-Protein Ligases Biology 03 medical and health sciences chemistry.chemical_compound Internal medicine Endopeptidases medicine Animals Humans Liver X receptor Cholesterol PCSK9 Cholesterol LDL Sterol regulatory element-binding protein Evolocumab 030104 developmental biology Endocrinology Receptors LDL chemistry LDL receptor HMG-CoA reductase biology.protein lipids (amino acids peptides and proteins) Mevalonate pathway Cardiology and Cardiovascular Medicine |
| Zdroj: | Circulation Research. 118:371-373 |
| ISSN: | 1524-4571 0009-7330 |
| DOI: | 10.1161/circresaha.116.308191 |
| Popis: | Forty years ago, Akira Endo discovered that a fungal metabolite inhibits 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the rate limiting step of the mevalonate pathway and therefore cholesterol biosynthesis, and initiated the development of statins to treat hypercholesterolemia. Subsequent work by the group of Michael Brown and Joseph Goldstein identified the low density lipoprotein receptor (LDLR) as the central player in the elaborate homeostatic controls that occur in response to statin-induced cellular cholesterol depletion. In a bid to acquire more cholesterol, hepatocytes (to which the drugs are mostly targeted) respond by transcriptionally upregulating LDLR via the sterol regulatory element binding protein (SREBP) transcription factors, thereby clearing more circulating LDL, and thus lowering blood cholesterol levels.1 Statins are effective, both clinically and economically, but decades of its widespread use have made apparent some infrequent side effects, including myopathy and an increased onset of diabetes. In addition to producing cholesterol, the mevalonate pathway is also essential to protein isoprenylation and N -glycosylation, which may account for both the beneficial and adverse side effects of statins. A drug that posttranscriptionally increases the LDLR would therefore be the ideal hypocholesterolemic agent, and thus enter proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Alirocumab and evolocumab markedly lower LDL-cholesterol but are expensive, owing to the fact that they are monoclonal antibodies directed against PCSK9. A small molecule inhibitor of an enzyme could be more affordable, but unfortunately, PCSK9’s degradative effect on LDLR is not attributable to its subtilase activity2 and PCSK9 has not proven amenable to a small molecule approach. Article, see p 410 The LDLR protein abundance is also regulated by the inducible degrader of LDLR (IDOL), which is upregulated in conditions of sterol excess as the IDOL gene is a transcriptional gene target for the liver X receptor (LXR).3 While at an earlier … |
| Databáze: | OpenAIRE |
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