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. www.cellmetabolism.org


'"/>

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:
*Name:
*Comment:
*Email:


(Date:2/8/2017)... (NASDAQ: AWRE ), a leading supplier of biometrics ... and year ended December 31, 2016. Revenue ... to $6.9 million in the same quarter last year. Operating ... compared to $2.6 million in the fourth quarter of 2015. ... million, or $0.02 per diluted share, which compares to $1.8 ...
(Date:2/8/2017)... YORK , Feb. 7, 2017 ... Driven largely by the confluence of organizations, desires ... distaste for knowledge-based systems (password and challenge questions), ... industrial, and government systems. The market is driven ... a demarcation between consumer and enterprise uses cases, ...
(Date:2/7/2017)... Feb. 7, 2017   MedNet Solutions , an ... spectrum of clinical research, is pleased to announce that ... its innovative, highly flexible and award winning eClinical solution, ... iMedNet is a proven Software-as-a-Service (SaaS) clinical ... Capture (EDC), but also delivers an entire suite of ...
Breaking Biology News(10 mins):
(Date:2/17/2017)... , Feb. 17, 2017  If only one ... had a mutation-conferring resistance to chemotherapy, thousands of ... research has focused on finding these mutations in ... from circulating tumor DNA in blood — to ... therapeutics. Unfortunately, however, detecting these genetic ...
(Date:2/16/2017)... Brussels, Belgium (PRWEB) , ... February 16, 2017 , ... ... Development (SIOTAD) framework primarily aimed at the agricultural industry. Pilot studies are about to ... phytosanitary products through IoT, Big Data and 5G innovations. The concept is expected to ...
(Date:2/16/2017)... and GREENWICH, Conn. ... private investment firm focused on venture growth investments ... promotion of Josh Richardson , M.D. to ... investments in biotechnology companies.  He is a board ... important roles in Longitude,s investments in Aimmune Therapeutics, ...
(Date:2/16/2017)... , Feb. 16, 2017 ... "Synthetic Biology: Global Markets" report to their ... ... products (synthetic genes, biobrick parts, delivery plasmids, chassis organisms, ... synthesis and assembly, genome editing, bioinformatics and specialty media) ...
Breaking Biology Technology: