Navigation Links
Insight into natural cholesterol control suggests novel cholesterol-lowering therapy

New work reported in the March issue of Cell Metabolism has provided insight into a key mechanism by which cells limit cholesterol synthesis. The finding suggests a novel approach to the development of cholesterol-lowering drugs that may boost the effect of statins, one of the most prescribed cholesterol inhibitors, according to researchers at the University of Texas Southwestern Medical Center.

Cells obtain cholesterol, an important component of cell membranes, by building it internally or by taking it up from the bloodstream. The cholesterol-building process involves more than 25 enzymes, including one called HMG CoA reductase, and many layers of regulatory control, said Russell DeBose-Boyd, senior author of the study.

Scientists have long known that cells respond to a high cholesterol diet by shutting down its internal synthesis, he explained. However, the molecular mechanisms by which cholesterol and other related compounds exert that self-control have only more recently begun to emerge.

The researchers now demonstrate that lanosterol--an intermediate compound in the synthetic pathway--mediates feedback control over the rate of cholesterol production by stimulating the degradation of cholesterol-building reductase. The availability of reductase, which functions early in the synthetic process, largely determines the rate of cellular cholesterol production, Debose-Boyd said.

When added to intact cells and cellular components in test tubes, lanosterol led other proteins to mark reductase for destruction by attaching a protein called ubiquitin in a process called ubiquitination. Ubiquitination is a common mechanism for stimulating protein degradation. Cholesterol itself had no such effect on reductase, even at much greater concentrations, they found.

"The current results demonstrate a direct role for lanosterol as a selective, physiologic regulator of reductase ubiquitination and degradation," said DeBose-Boyd. That effect woul d, in turn, control the rate of cholesterol production.

"In addition to the biological significance, the findings have important clinical implications for cholesterol control," he said.

Cholesterol-lowering statins--taken by an estimated 10 million people each day to protect against coronary artery disease and reduce the incidence of heart attacks--limit cholesterol synthesis by inhibiting reductase function, he said. As a result, cells take up more cholesterol from the bloodstream, lowering its concentration there.

However, inhibition of reductase function by statins also limits the availability of regulatory intermediates that govern reductase activity, contributing to a major increase in active reductase that becomes progressively harder to control, according to the researchers. The new findings suggest that drugs that mimic lanosterol--given along with statins--may improve the drugs' long-term ability to lower cholesterol by stimulating reductase degradation.


The other members of the research team include Bao-Liang Song and Russell A. DeBose-Boyd from University of Texas Southwestern Medical Center; and Norman B. Javitt from New York University School of Medicine. The work was supported by research grants from the National Institutes of Health (HL20948), Perot Family Foundation, and W.M. Keck Foundation. R.A.D.-B. is the recipient of a National Institutes of Health Mentored Minority Faculty Development Award (HL70441) and an Established Investigator Award from the American Heart Association.

Bao-Liang Song, Norman B. Javitt, and Russell A. DeBose-Boyd: "Insig-mediated degradation of HMG CoA reductase stimulated by lanosterol, an intermediate in the synthesis of cholesterol"

Publishing in Cell Metabolism, Volume 1, Number 3, March 2005, pages 179-189.


Source:Cell Press

Related biology news :

1. Fundamental Finding Yields Insight into Stem Cells, Cancer; Opens Door to Drug Discovery
2. New Insights Into HIV Immunity Suggest Alternative Approach to Vaccines
3. Insight into DNAs weakest links may yield clues to cancer biology
4. Insight into our sight: A new view on the evolution of the eye lens
5. Insight into the processes of positive and negative learners
6. Large-scale Computer Simulations Reveal New Insights Into Antibiotic Resistance
7. What Makes The Brain Tick, Tick, Tick: Researchers Gaining New Insights Into Brains Internal Clock
8. Genetically modified natural killer immune cells attack, kill leukemia cells
9. UCSD discovery may help extend life of natural pesticide
10. UCLA scientists store materials in cells natural vaults
11. Man-made wetlands effectiveness similar to natural marsh
Post Your Comments:

(Date:8/15/2017)... Aug. 15 2017   ivWatch LLC , a medical device ... therapy, today announced receipt of its ISO 13485 Certification, the global ... International Organization for Standardization (ISO®). ... ivWatch Model 400 Continuous Monitoring device for the early detection of ... "This is an important milestone ...
(Date:6/14/2017)... (NYSE: IBM ) is introducing several innovative partner startups ... collaboration between startups and global businesses, taking place in ... nine startups will showcase the solutions they have built with ... France is one of the ... percent increase in the number of startups created between 2012 ...
(Date:5/6/2017)... SINGAPORE , May 5, 2017 ... has just announced a new breakthrough in biometric ... that exploits quantum mechanical properties to perform ... new smart semiconductor material created by Ram Group ... across finance, entertainment, transportation, supply chains and security. ...
Breaking Biology News(10 mins):
(Date:10/12/2017)... ... October 12, 2017 , ... They call it the ... network, a depiction of a system of linkages and connections so complex and ... professor of computer science at Worcester Polytechnic Institute (WPI) and director of the ...
(Date:10/12/2017)... JOHNSTON, Iowa (PRWEB) , ... October 12, 2017 ... ... company based in Vilnius, Lithuania, announced today that they have entered into a ... collaboration is to provide CRISPR researchers with additional tools for gene editing across ...
(Date:10/12/2017)... , ... October 12, 2017 , ... ... Wound Market with the addition of its newest module, US Hemostats & Sealants. ... for thrombin hemostats, absorbable hemostats, fibrin sealants, synthetic sealants and biologic sealants used ...
(Date:10/12/2017)... ... October 12, 2017 , ... ... launched Rosalind™, the first-ever genomics analysis platform specifically designed for life science ... in honor of pioneering researcher Rosalind Franklin, who made a major contribution ...
Breaking Biology Technology: