Impaired cholesterol metabolism in the mouse model of cystic fibrosis. A preliminary study

Abstract

This study aims to investigate cholesterol metabolism in a mouse model with cystic fibrosis (CF) by the comparison of affected homozygous versuswild type(WT) mice. In particular, we evaluated the effects of a diet enriched with cholesterol in both mice groups in comparison with the normal diet. To this purpose, beyond serum and liver cholesterol, we analyzed serum phytosterols as indirect markers of intestinal absorption of cholesterol, liver lathosterol as indirect marker ofde novocholesterol synthesis, liver cholestanol (a catabolite of bile salts synthesis) and the liver mRNA levels ofLDL receptor(LDLR),3-hydroxy-3-methylglutaryl-CoA reductase(HMG-CoAR),acyl CoA:cholesterol acyl transferase 2(ACAT2),cytochrome P450 7A1(CYP7A1) andtumor necrosis factor alpha(TNFα). CF mice showed lower intestinal absorption and higher liver synthesis of cholesterol than WT mice. In WT mice, the cholesterol supplementation inhibits the synthesis of liver cholesterol and enhances its catabolism, while in CF mice we did not observe a reduction ofLDLRandHMG-CoARexpression (probably due to an altered feed-back), causing an increase of intracellular cholesterol. In addition, we observed a further increase (5-fold) inTNFαmRNA levels. This preliminary study suggests that in CF mice there is a vicious circle in which the altered synthesis/secretion of bile salts may reduce the digestion/absorption of cholesterol. As a result, the liver increases the biosynthesis of cholesterol that accumulates in the cells, triggering inflammation and further compromising the metabolism of bile salts.