on April 14, 2005
Published online before print April 14, 2005, doi: 10.1161/01.ATV.0000166548.65753.1e
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on February 3, 2005
Accepted on April 5, 2005
ACAT2 Is a Target for Treatment of Coronary Heart Disease Associated With Hypercholesterolemia
Lawrence L. Rudel *;
From the Lipid Sciences Research Program (L.L.R., R.L.), the Departments of Pathology and Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC; and the Center for Metabolism and Endocrinology (P.P.), Department of Medicine, Karolinska Institute at Karolinska University Hospital, Huddinge, Sweden.
* To whom correspondence should be addressed. E-mail: lrudel{at}wfubmc.edu.
Abstract--The inhibition of intracellular cholesterol esterification as a means to prevent atherosclerosis has been considered to have potential for many years. Two different ACAT enzymes were discovered about 7 years ago, and it has become clear that the two enzymes provide separate physiologic functions. Much has been learned from mice with gene deletions for either ACAT1 or ACAT2. Deletion of ACAT2 has consistently been atheroprotective whereas deletion of ACAT1 has been varyingly problematic. ACAT1 functions in converting cellular cholesterol into cholesteryl ester in response to cholesterol abundance inside the cells. In atherosclerotic lesions, where macrophages ingest excess cholesterol, the ability to esterify the newly-acquired cholesterol seems important for cell survival. Inhibition of ACAT1 may bring undesired consequences with destabilization of cellular membrane function upon cholesterol accumulation leading to macrophage cell death. In contrast, ACAT2 is expressed only in hepatocytes and enterocytes, where ACAT1 is silent, and appears to provide cholesteryl esters for transport in lipoproteins. These two cell types have an abundance of additional mechanisms for disposing of cholesterol so that depletion of ACAT2 does not signal apoptosis. At the present time, the bulk of the available data suggest that the strategy seeming to bear the most potential for treatment of coronary heart disease associated with hypercholesterolemia would be to specifically inhibit ACAT2.
This article has been cited by other articles:
 |
|
 |
|
  A. Das, M. A. Davis, and L. L. Rudel Identification of putative active site residues of ACAT enzymes J. Lipid Res., August 1, 2008; 49(8): 1770 - 1781. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Parini, U. Gustafsson, M. A. Davis, L. Larsson, C. Einarsson, M. Wilson, M. Rudling, H. Tomoda, S. Omura, S. Sahlin, et al. Cholesterol Synthesis Inhibition Elicits an Integrated Molecular Response in Human Livers Including Decreased ACAT2 Arterioscler. Thromb. Vasc. Biol., June 1, 2008; 28(6): 1200 - 1206. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Brown, T. A. Bell III, H. M. Alger, J. K. Sawyer, T. L. Smith, K. Kelley, R. Shah, M. D. Wilson, M. A. Davis, R. G. Lee, et al. Targeted Depletion of Hepatic ACAT2-driven Cholesterol Esterification Reveals a Non-biliary Route for Fecal Neutral Sterol Loss J. Biol. Chem., April 18, 2008; 283(16): 10522 - 10534. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Das, M. A. Davis, H. Tomoda, S. Omura, and L. L. Rudel Identification of the Interaction Site within Acyl-CoA:Cholesterol Acyltransferase 2 for the Isoform-specific Inhibitor Pyripyropene A J. Biol. Chem., April 18, 2008; 283(16): 10453 - 10460. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. Hutchins, R. M. Barkley, and R. C. Murphy Separation of cellular nonpolar neutral lipids by normal-phase chromatography and analysis by electrospray ionization mass spectrometry J. Lipid Res., April 1, 2008; 49(4): 804 - 813. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Spector and W. G. Haynes LDL Cholesteryl Oleate: A Biomarker for Atherosclerosis? Arterioscler. Thromb. Vasc. Biol., June 1, 2007; 27(6): 1228 - 1230. [Full Text] [PDF]
|
|
|
|
|
|
S. N. Mathur, K. R. Watt, and F. J. Field Regulation of intestinal NPC1L1 expression by dietary fish oil and docosahexaenoic acid J. Lipid Res., February 1, 2007; 48(2): 395 - 404. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. A. Bell III, J. M. Brown, M. J. Graham, K. M. Lemonidis, R. M. Crooke, and L. L. Rudel Liver-Specific Inhibition of Acyl-Coenzyme A:Cholesterol Acyltransferase 2 With Antisense Oligonucleotides Limits Atherosclerosis Development in Apolipoprotein B100-Only Low-Density Lipoprotein Receptor-/- Mice Arterioscler. Thromb. Vasc. Biol., August 1, 2006; 26(8): 1814 - 1820. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Fazio and M. Linton Failure of ACAT inhibition to retard atherosclerosis. N. Engl. J. Med., March 23, 2006; 354(12): 1307 - 1309. [Full Text] [PDF]
|
|