The UPS and downs of cholesterol homeostasis

• Published in: Trends in biochemical sciences (Amsterdam. Regular ed.) Vol. 39; no. 11; pp. 527 - 535
• Main Authors: Sharpe, Laura J., Cook, Emma C.L., Zelcer, Noam, Brown, Andrew J.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.11.2014
• Subjects: ATP-Binding Cassette Transporters - metabolism; cholesterol; Cholesterol - metabolism; degradation; E3 ubiquitin ligase; Homeostasis; Humans; Hydroxymethylglutaryl CoA Reductases - metabolism; Models, Biological; proteasome; Proteasome Endopeptidase Complex - metabolism; Receptors, LDL - metabolism; Squalene Monooxygenase - metabolism; Transcription Factors - metabolism; Ubiquitin - metabolism; Ubiquitin-Protein Ligases - metabolism; ubiquitylation; proteasome; cholesterol; degradation; E3 ubiquitin ligase; ubiquitylation
• ISSN: 0968-0004; 1362-4326
• DOI: 10.1016/j.tibs.2014.08.008

•The ubiquitin-proteasome system affects all aspects of cholesterol homeostasis.•Many E3 ligases have been shown to play a role in cholesterol regulation.•Specific targeting of E3 ligases is a potential approach to treat dyslipidemia.•Deubiquitylases are emerging as important effectors of cholesterol metabolism. An emerging theme in the regulation of cholesterol homeostasis is the role of the ubiquitin proteasome system (UPS), through which proteins are ubiquitylated and then degraded in response to specific signals. The UPS controls all aspects of cholesterol metabolism including its synthesis, uptake, and efflux. We review here recent work uncovering the ubiquitylation and degradation of key players in cholesterol homeostasis. This includes the low-density lipoprotein (LDL) receptor, transcription factors (sterol regulatory element binding proteins and liver X receptors), flux-controlling enzymes in cholesterol synthesis (3-hydroxy-3-methylglutaryl-CoA reductase and squalene monooxygenase), and cholesterol exporters (ATP-binding cassette transporters ABCA1 and ABCG1). We explore which E3 ligases are involved, and identify areas deserving of further research.