Reduced biliary sterol output with no change in total faecal excretion in mice expressing a human apolipoprotein A-I variant

Background/Aims: Apolipoprotein (apo)A-IMilano, is a molecular variant of apoA-Iwild-type, associated with dramatically low HDL-cholesterol levels, but no increased risk for cardiovascular disease. In view of the present uncertainties on the role of apoA-I in liver cholesterol removal by way of bile acids and neutral sterols, and of the greater capacity of apoA-IMilano to remove arterial cholesterol, biliary sterol metabolism was evaluated in transgenic mice expressing apoA-IMilano. Methods: ApoA-IMilano mice were fed a high-cholesterol/high-fat diet, and compared with human apoA-Iwild-type mice. Plasma lipid levels, hepatic bile flow and composition, hepatic and intestinal cholesterol and bile acid content, and faecal sterol content were measured. Moreover, the expression of hepatic ABCA1, SR-B1 and that of hepatic and intestinal genes involved in bile acid metabolism were evaluated. Results: The dietary treatment led to a strong elevation in HDL-cholesterol levels in A-IMilano mice, associated with an increased expression of hepatic ABCA1. ApoA-IMilano mice showed lower cholesterol output from the liver compared with apoA-Iwild-type mice, in the absence of liver sterol accumulation. Faecal excretion of neutral sterols and bile acids was similar in the two mouse lines. Conclusions: In spite of a different response to the dietary challenge, with an increased ABCA1 expression and a lower hepatic cholesterol output in apoA-IMilano mice, the net sterol excretion is comparable in the two transgenic lines.