Featured Research

from universities, journals, and other organizations

New way of fighting high cholesterol upends assumptions

Date:
September 27, 2012
Source:
University of California, San Diego Health Sciences
Summary:
Atherosclerosis has been presumed to be the consequence of complicated interactions between overabundant cholesterol and resulting inflammation in the heart and blood vessels. Researchers now say the relationship is not exactly what it appears, and that a precursor to cholesterol actually suppresses inflammatory response genes. This precursor molecule could provide a new target for drugs designed to treat atherosclerosis.

When macrophages take up massive amounts of cholesterol they form “foam cells,” characterized by multiple lipid droplets (stained red).
Credit: Image courtesy of Marten Hoeksema, University of Amsterdam.

Atherosclerosis -- the hardening of arteries that is a primary cause of cardiovascular disease and death -- has long been presumed to be the fateful consequence of complicated interactions between overabundant cholesterol and resulting inflammation in the heart and blood vessels.

However, researchers at the University of California, San Diego School of Medicine, with colleagues at institutions across the country, say the relationship is not exactly what it appears, and that a precursor to cholesterol actually suppresses inflammatory response genes. This precursor molecule could provide a new target for drugs designed to treat atherosclerosis, which kills tens of thousands of Americans annually.

The findings are published in the September 28, 2012 issue of Cell.

Lurking within our arterial walls are immune system cells called macrophages (Greek for "big eater") whose essential function is to consume other cells or matter identified as foreign or dangerous. "When they do that, it means they consume the other cell's store of cholesterol," said Christopher Glass, MD, PhD, a professor in the Departments of Medicine and Cellular and Molecular Medicine and senior author of the Cell study. "As a result, they've developed very effective ways to metabolize the excess cholesterol and get rid of it."

But some macrophages fail to properly dispose of the excess cholesterol, allowing it to instead accumulate inside them as foamy lipid (fat) droplets, which gives the cells their particular name: macrophage foam cells.

These foam macrophages produce molecules that summon other immune cells and release molecules, signaling certain genes to launch an inflammatory response. Glass said conventional wisdom has long assumed atherosclerotic lesions -- clumps of fat-laden foam cells massed within arterial walls -- were the unhealthy consequence of an escalating association between unregulated cholesterol accumulation and inflammation.

Glass and colleagues wanted to know exactly how cholesterol accumulation led to inflammation, and why the macrophages failed to do their job. Using specialized mouse models that produced abundant macrophage foam cells, they made two unexpected discoveries that upend previous assumptions about how lesions form and how atherosclerosis might be more effectively treated.

"The first is that foam cell formation suppressed activation of genes that promote inflammation. That's exactly the opposite of what we thought happened," said Glass. "Second, we identified a molecule that helps normal macrophages manage cholesterol balance. When it's in abundance, it turns on cellular pathways to get rid of cholesterol and turns off pathways for producing more cholesterol."

That molecule is desmosterol -- the final precursor in the production of cholesterol, which cells make and use as a structural component of their membranes. In atherosclerotic lesions, Glass said the normal function of desmosterol appears to be "crippled."

"That's the next thing to study; why that happens," Glass said, hypothesizing that the cause may be linked to overwhelming, pro-inflammatory signals coming from proteins called Toll-like receptors on macrophages and other cells that, like macrophages, are critical elements of the immune system.

The identification of desmosterol's ability to reduce macrophage cholesterol presents researchers and drug developers with a potential new target for reducing the risk of atherosclerosis.

Glass noted that a synthetic molecule similar to desmosterol already exists, offering an immediate test-case for new studies. In addition, scientists in the 1950s developed a drug called triparanol that inhibited cholesterol production, effectively boosting desmosterol levels. The drug was sold as a heart disease medication, but later discovered to cause severe side effects, including blindness from an unusual form of cataracts. It was pulled from the market and abandoned.

"We've learned a lot in 50 years," said Glass. "Maybe there's a way now to create a new drug that mimics the cholesterol inhibition without the side effects."

Co-authors are first author Nathanael J. Spann, Norihito Shibata, Donna Reichart, Jesse N. Fox and Daniel Heudobler, UCSD Department of Cellular and Molecular Medicine; Lana X. Garmire, UCSD Department of Bioengineering; Jeffrey G. McDonald and David W. Russell, Department of Molecular Genetics, UT Southwestern Medical Center; David S. Myers, Stephen B. Milne and Alex Brown, Department of Pharmacology, Vanderbilt Institute of Chemical Biology; Iftach Shaked and Klaus Ley, La Jolla Institute of Allergy and Immunology; Christian R.H. Raetz, Department of Biochemistry, Duke University School of Medicine; Elaine W. Wang, Samuel L. Kelly, M. Cameron Sullards and Alfred H. Merrill, Jr., Schools of Biology, Chemistry and Biochemistry and the Parker H. Petit Institute of Bioengineering and Bioscience, George Institute of Technology; Edward A. Dennis, UCSD Department of Chemistry and Biochemistry; Andrew C. Li, Sotirios Tsimikas and Oswald Quehenberger, UCSD Department of Medicine; Eoin Fahy, UCSD Department of Bioengineering; and Shankar Subramaniam, UCSD Departments of Cellular and Molecular Medicine, Bioengineering and Chemistry and Biochemistry.

Funding for this research came, in part, from National Institutes of Health grants GM U54069338 (to the LIPID MAPS Consortium), P01 HC088093 and P01 DK074868.


Story Source:

The above story is based on materials provided by University of California, San Diego Health Sciences. Note: Materials may be edited for content and length.


Journal Reference:

  1. Nathanael J. Spann, Lana X. Garmire, Jeffrey G. McDonald, David S. Myers, Stephen B. Milne, Norihito Shibata, Donna Reichart, Jesse N. Fox, Iftach Shaked, Daniel Heudobler, Christian R.H. Raetz, Elaine W. Wang, Samuel L. Kelly, M. Cameron Sullards, Robert C. Murphy, Alfred H. Merrill, H. Alex Brown, Edward A. Dennis, Andrew C. Li, Klaus Ley, Sotirios Tsimikas, Eoin Fahy, Shankar Subramaniam, Oswald Quehenberger, David W. Russell, Christopher K. Glass. Regulated Accumulation of Desmosterol Integrates Macrophage Lipid Metabolism and Inflammatory Responses. Cell, 2012; 151 (1): 138 DOI: 10.1016/j.cell.2012.06.054

Cite This Page:

University of California, San Diego Health Sciences. "New way of fighting high cholesterol upends assumptions." ScienceDaily. ScienceDaily, 27 September 2012. <www.sciencedaily.com/releases/2012/09/120927123640.htm>.
University of California, San Diego Health Sciences. (2012, September 27). New way of fighting high cholesterol upends assumptions. ScienceDaily. Retrieved April 23, 2014 from www.sciencedaily.com/releases/2012/09/120927123640.htm
University of California, San Diego Health Sciences. "New way of fighting high cholesterol upends assumptions." ScienceDaily. www.sciencedaily.com/releases/2012/09/120927123640.htm (accessed April 23, 2014).

Share This



More Health & Medicine News

Wednesday, April 23, 2014

Featured Research

from universities, journals, and other organizations


Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

    Health News

    Environment News

    Technology News



      Save/Print:
      Share:  

      Free Subscriptions


      Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

      Get Social & Mobile


      Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

      Have Feedback?


      Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
      Mobile iPhone Android Web
      Follow Facebook Twitter Google+
      Subscribe RSS Feeds Email Newsletters
      Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins