Policosanol (Reduchole22®) attenuates hypercholesterolemia via modulation of cholesterol biosynthesis and lipid metabolism in a high-fat diet-induced mouse model

Policosanol, a mixture of long-chain aliphatic alcohols derived from sugarcane, is a promising nutraceutical for lowering blood cholesterol levels. Previous studies have reported cholesterol-lowering mechanisms, such as adenosine monophosphate-activated protein kinase (AMPK) activation, HMG-CoA reductase (HMGCR) inhibition, LDL receptor upregulation, and enhanced bile acid excretion. However, the underlying mechanisms related to additional aspects of cholesterol biosynthesis and lipid metabolism have not been fully elucidated. In this study, we evaluated the cholesterol-lowering effects of policosanol (Reduchole22®), a policosanol purified from sugarcane ethanol extract, in a high-fat diet (HFD)-induced mouse model. Our in vivo results showed that policosanol significantly reduced the atherogenic index in plasma and inhibited key enzymes involved in cholesterol synthesis, including HMGCR and acetyl-CoA acetyltransferase 1 (ACAT1), in both hepatic and arterial tissues. Our results confirmed previously reported mechanisms, including significant reductions in the atherogenic index, HMGCR and acetyl-CoA acetyltransferase 1 (ACAT1) inhibition, increased ATP-binding cassette transporter G5 (ABCG5) expression, and enhanced cholesterol 7α-hydroxylase (CYP7A1) activity, thus promoting cholesterol excretion. Notably, our study uniquely elucidates policosanol’s modulation of cholesteryl ester transfer protein (CETP), lecithin-cholesterol acyltransferase (LCAT), and paraoxonase 1 (PON1), providing deeper insights into HDL function, antioxidative defense mechanisms, and comprehensive lipid metabolism regulation. Our findings highlight policosanol as a distinct functional food ingredient for managing hypercholesterolemia and cardiovascular disease.