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New molecular targets for cholesterol-lowering therapy
N N Izzat1, M E Deshazer, D S Loose-Mitchell
1Department of Integrative Biology and Pharmacology, University of Texas Health Sciences Center, Houston, Texas 77225, USA.
Insights
Cholesterol-lowering statins significantly reduce cardiovascular and total mortality risk. New therapies targeting bile acid transport and cholesterol absorption offer additional strategies for managing cholesterol levels.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
Background:
- Randomized clinical trials confirm that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) reduce cardiovascular and total mortality.
- Risk reduction is observed across diverse patient populations, including those with and without pre-existing cardiovascular disease or varying plasma cholesterol levels.
Purpose of the Study:
- To review the established benefits of cholesterol-lowering therapies.
- To identify and discuss novel molecular targets for future cholesterol-lowering drug development.
Main Methods:
- Review of randomized clinical trials on statin efficacy.
- Identification and description of emerging therapeutic targets, including the Na(+)-dependent bile acid transporter, cholesterol absorption pathways, and transcriptional regulation of cholesterol 7alpha-hydroxylase.
Main Results:
- Statins effectively lower plasma cholesterol, slow atherosclerosis progression, and reduce ischemic events, potentially to levels below 100 mg/dl.
- Novel targets offer alternative mechanisms for cholesterol reduction beyond statin pathways.
Conclusions:
- Cholesterol-lowering treatment is a proven strategy for reducing mortality.
- Emerging targets like the bile acid transporter and cholesterol absorption mechanisms present promising avenues for new therapeutic interventions.
Abstract:
The use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) in randomized clinical trials has established that cholesterol-lowering treatment reduces the risk of both cardiovascular and total mortality. This reduction in risk occurs in patients with or without existing cardiovascular disease and in patients with high or average plasma cholesterol concentrations. Aggressive treatment to lower plasma cholesterol has been shown to slow progression of atherosclerosis and in some instances may be as successful as angioplasty in reducing ischemic events. These studies suggest that reduction of plasma cholesterol to levels even below 100 mg/dl might be desirable. New targets for cholesterol-lowering therapy with mechanisms of action different from the statins have been identified. One of these targets is the Na(+)-dependent bile acid transporter that is expressed in the terminal ileum. This protein is responsible for recycling bile acids from the intestine to the liver. Several compounds that demonstrate the ability to decrease transporter activity and to lower plasma cholesterol have been investigated. Absorption of cholesterol from the small intestine is another potential target. Compounds that inhibit cholesterol absorption may act by interacting stoichiometrically with cholesterol within the intestinal lumen or substoichiometrically, presumably within the enterocyte. Finally, the transcriptional regulation of cholesterol 7alpha-hydroxylase by members of the nuclear receptor superfamily provides at least two other molecular targets for cholesterol-lowering drugs.