>>SAN DIEGO, Calif., Aug. 20 /PRNewswire-FirstCall/ -- Scientists at X-Ceptor Therapeutics, Inc., along with colleagues at the Howard Hughes Medical Institutes at the University of California, Los Angeles and University of Texas-Southwestern Medical Center at Dallas have established a direct protective role between the liver X receptors (LXRs) and the pathogenesis of cardiovascular disease, the number one cause of morbidity and mortality in the western world. This discovery will be published online this week in the Proceedings of the National Academy of Sciences (PNAS).
The LXRs (LXR alpha and LXR beta) are nuclear hormone receptors that act as key sensors of cholesterol in the body and regulate expression of genes critical to the maintenance of blood cholesterol levels. Elevated plasma cholesterol can lead to atherosclerosis, which occurs when macrophages enter the inside of the artery wall and initiate the development of atherosclerotic plaques that can trigger heart attack or stroke by blocking blood vessels.
Researchers demonstrated that the selective loss of macrophage LXR activity significantly increased atherosclerotic lesion development. "This demonstrates that the LXRs are protective or anti-atherogenic and thereby represent a novel molecular target for the treatment of cardiovascular disease," stated Dr. Richard Heyman, Chief Scientific Officer at X-Ceptor Therapeutics. These studies were performed by replacing normal macrophages with LXR-deficient macrophages in mice using bone marrow transplantation. The results demonstrate that these receptors function as endogenous inhibitors of atherosclerosis. Although previous studies have shown that LXRs are important regulators of cholesterol levels in the body, this study is the first to show a direct link between macrophage LXR activity and its role in the inhibition of atherosclerosis.
Researchers have shown that modulators of LXRs increase the expression of genes called ABC transporters, which promote a process known as "reverse cholesterol transport." This process eliminates excess cholesterol from tissues, particularly from the artery wall, thereby preventing the development of atherosclerotic lesions. The findings provide strong support for novel LXR-based therapeutic approaches that target cardiovascular disease. "There has been a tremendous interest in the development of LXR-based drugs which, unlike the statins, can regulate cholesterol levels through a unique mechanism of action. Such therapeutics could potentially be co-administered in conjunction with statin therapy or to patients that do not respond to conventional statin mono-therapy," stated Dr. Ira Schulman, senior author and Director of Biology at X-Ceptor Therapeutics.
Cardiovascular disease was attributable to over 950,000 deaths in the United States in 1999 alone. Approximately fifty percent of the adult population has elevated levels of cholesterol. Currently, there is no effective treatment to increase reverse cholesterol transport and HDL levels.
X-Ceptor Therapeutics, Inc. is a drug discovery company focused on the development of novel small molecule drugs that modulate nuclear receptors. The company has developed an integrated drug discovery process that is designed specifically for the nuclear receptor gene family as a comprehensive approach to rapidly advance small molecule drug discovery programs from gene to clinic. In 2001, the company entered into a three-year collaboration with Sankyo Co., Ltd. to discover and develop selective modulators of LXR.
More information on the company is available at www.x-ceptor.com .<<
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