Effect of the lipid-lowering drug lifibrol on lipid metabolism in rat macrophages and in atherosclerotic arteries from swine and WHHL rabbits, in vitro. Implications in atherogenesis.
The effects of lifibrol on lipid metabolism in rat macrophages and swine and rabbit aortae were investigated. Resident peritoneal macrophages isolated from rats pretreated with lifibrol (50 mg/kg/7 days) showed a decreased capacity to synthesize cholesteryl esters from labeled precursors ([1-14C]oleate and [4-14C]cholesterol). Macrophages isolated similarly from non-treated rats demonstrated the ability to take up [14C]lifibrol, in vitro. Modification of lipid metabolism in atherosclerotic aortae from swine and Watanabe heritable hyperlipidemic (WHHL) rabbits was also observed when the tissues were incubated in vitro in the presence of exogenous lifibrol. Concentrations of lifibrol of up to 50 micrograms/mL in the incubations selectively reduced the formation of cholesteryl esters from [1-14C]acetate by 60-75%, whereas higher concentrations (100 micrograms/mL) resulted in a generalized inhibition of lipid biosynthesis of about 50% and of cholesteryl ester formation by up to 90%. The ability of lifibrol to directly affect these targets (i.e. macrophages and arterial tissue) has implications that extend beyond its confirmed plasma cholesterol-lowering activity since early stages of the atherogenic process involve an overall increase in arterial lipid synthesis and cholesteryl ester accumulation by monocyte-macrophages that infiltrate the vessel wall from blood.