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Journal of Lipid Research, Vol. 51, 202-209, January 2010
Copyright © 2010 by American Society for Biochemistry and Molecular Biology

Patient-Oriented and Epidemiological Research

Cholesterol absorption and synthesis markers in individuals with and without a CHD event during pravastatin therapy: insights from the PROSPER trial

Nirupa R. Matthan^1,*,, Nancy Resteghini^*, Michele Robertson, Ian Ford, James Shepherd^**, Chris Packard^**, Brendan M. Buckley, J. Wouter Jukema, Alice H. Lichtenstein, Ernst J. Schaefer^* and for the PROSPER Group²

^* Cardiovascular Research Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA
Friedman School of Nutrition, Science and Policy at Tufts University, and Cardiovascular Nutrition Laboratory, Boston, MA
Robertson Centre for Biostatistics, University of Glasgow, Glasgow, Scotland
^** University Department of Pathological Biochemistry, North Glasgow University NHS Trust, Glasgow, Scotland
European Centre for Clinical Trials in Rare Diseases, University College Cork, Ireland
Department of Cardiology, Leiden University Medical Center, The Netherlands

¹ To whom correspondence should be addressed. e-mail: nirupa.matthan{at}tufts.edu

Cholesterol homeostasis, defined as the balance between absorption and synthesis, influences circulating cholesterol concentrations and subsequent coronary heart disease (CHD) risk. Statin therapy targets the rate-limiting enzyme in cholesterol biosynthesis and is efficacious in lowering CHD events and mortality. Nonetheless, CHD events still occur in some treated patients. To address differences in outcome during pravastatin therapy (40 mg/day), plasma markers of cholesterol synthesis (desmosterol, lathosterol) and fractional cholesterol absorption (campesterol, sitosterol) were measured, baseline and on treatment, in the Prospective Study of Pravastatin in the Elderly at Risk trial participants with (cases, n = 223) and without (controls, n = 257) a CHD event. Pravastatin therapy decreased plasma LDL-cholesterol and triglycerides and increased HDL-cholesterol concentrations to a similar extent in cases and controls. Decreased concentrations of the cholesterol synthesis markers desmosterol (–12% and –11%) and lathosterol (–50% and –56%) and increased concentrations of the cholesterol absorption markers campesterol (48% and 51%) and sitosterol (25% and 26%) were observed on treatment, but the magnitude of change was similar between cases and controls. These data suggest that decreases in cholesterol synthesis in response to pravastatin treatment were accompanied by modest compensatory increases in fractional cholesterol absorption. The magnitude of these alterations were similar between cases and controls and do not explain differences in outcomes with pravastatin treatment.

Supplementary key words lipoproteins • lathosterol • desmosterol • phytosterols

Abbreviations: ABC, ATP-binding cassette; CHD, coronary heart disease; MI, myocardial infarct; PROSPER, Prospective Study of Pravastatin in the Elderly at Risk

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