Coffee polyphenols exert hypocholesterolemic effects in zebrafish fed a high-cholesterol diet

BACKGROUND Hypercholesterolemia is an important risk factor for the development of coronary artery disease. Some dietary polyphenols, such as coffee polyphenols (CPPs), reduce cholesterol levels. The mechanism of this cholesterol-lowering effect is not fully understood, although 5-CQA, a major component of CPPs, reportedly inhibits cholesterol biosynthesis. Here, we investigated the mechanism of the cholesterol-lowering effect of CPPs on the basis of cholesterol metabolism-related gene expression in the liver. We also examined the effects of CPPs on vascular lipid accumulation in zebrafish with high cholesterol diet-induced hypercholesterolemia. METHODS Over 14 weeks, adult zebrafish were fed a control diet, a high-cholesterol diet, or the latter diet supplemented with CPPs. To measure the extent of vascular lipid accumulation, for 10 days larval zebrafish (which are optically transparent) were fed these same diets with the addition of a fluorescent cholesteryl ester. RESULTS In adult zebrafish, addition of CPPs to a high-cholesterol diet significantly suppressed the increase in plasma and liver cholesterol levels seen when fish ingested the same diet lacking CPPs. Transcription levels of the liver genes hmgcra (encoding 3-hydroxy-3-methylglutaryl-coenzyme A reductase A, a rate-limiting enzyme in cholesterol biosynthesis) and mtp (encoding microsomal triglyceride transfer protein, a lipid transfer protein required for assembly and secretion of lipoproteins) were significantly lower in fish fed the CPP-containing diet than in fish fed the unsupplemented high-cholesterol diet. In contrast, the expression level of the liver gene cyp7a1a (encoding the cytochrome P450 polypeptide 1a of subfamily A of family 7, a rate-limiting enzyme for bile acid biosynthesis) increased significantly upon consumption of the CPP-containing diet. In larval fish, accumulation of fluorescently labeled cholesterol in the caudal artery was greatly reduced on the CPP-containing diet. CONCLUSIONS CPP ingestion suppressed cholesterol accumulation in the plasma, liver, and vascular system of zebrafish. Downregulation of cholesterol and lipoprotein synthesis and upregulation of bile acid synthesis in the liver may be the fundamental underlying mechanisms by which CPPs exert their hypocholesterolemic effects. CPP intake may help prevent and manage hypercholesterolemia in humans, and further investigations along these lines using a variety of CPP dose rates are warranted.