Epidemiological studies have suggested that hypercholesterolemia is an independent determinant of increased left ventricular (LV) mass. Because high -density lipoprotein and its major protein apolipoprotein A-I (apoA-I) mediate reverse cholesterol transport (RCT) and have cardiac protective effects, we hypothesized that the apoA-I mimetic peptide D-4F could promote RCT in cardiac tissue and decrease cardiac hypertrophy induced by hypercholesterolemia. Low -density lipoprotein receptor -null mice were fed by a Western diet for 18 weeks and then randomized to receive water, or D-4F 0.3 mg/mL, or D-4F 0.5 mg/mL added to drinking water for 6 weeks. After D-4F administration, an increase in high -density lipoprotein cholesterol and a decrease in low -density lipoprotein cholesterol, total cholesterol, and triglyceride in a trend toward doseresponsivity were found in cardiac tissue. Ultrasound biomicroscopy revealed a reduction in LV posterior wall end -diastolic dimension, and an increase in mitral valve E/A ratio and LV ejection fraction. Hematoxylin eosin staining showed reduced LV wall thickness and myocardial cell diameter. The protein levels of ABCA1 and LXRa were elevated in cardiac tissue of D-4F treated mice compared with the controls (P < 0.05). These results demonstrated that D -4F treatment reduced cardiac hypertrophy, and improved cardiac performance in low -density lipoprotein receptor -null mice fed a Western diet, presumably through the LXRcz-ABCA1 pathway associated with enhanced myocardial RCT.