Dietary cholic acid lowers plasma levels of mouse and human apolipoproteinA-I primarily via a transcriptional mechanism

To induce dietary atherosclerosis in mice, high-fat/high-cholesterol (HF) d iets are frequently supplemented with cholic acid (CA). This diet produces low plasma levels of high-density lipoprotein (HDL) and high levels of low- density lipoprotein (LDL). However, HF diets without any added CA, which mo re closely resemble human diets, increase levels of both HDL and LDL, sugge sting that CA may be responsible for the lowering of HDL. Our aim was to ex amine the potential mechanism responsible for the lowering of HDL. Nontrans genic (NTg) C57BL mice and apoA-I-transgenic (apoAI-Tg) mice, with greatly increased basal apoA-I and HDL levels, were used. Mice were fed the followi ng four diets: control (C), high-fat/high-cholesterol (HF), control and 1% cholate (CA) and HF + CA. Dietary CA reduced plasma HDL levels by 35% in NT g and 250% in apoAI-Tg mice, independent of the fat or cholesterol content of the diet. Hepatic apoA-I mRNA decreased 30% in NTg and 180% in apoAI-Tg mice. Hepatic apoA-I synthesis and apoA-I mRNA transcription rates also dec reased in parallel with apoA-I mRNA levels, suggesting that the CA-induced decreases in plasma apoA-I levels occurred primarily via decreasing apoA-I mRNA transcription rates. An HF diet increased HDL levels 1.8-fold in NTg a nd 1.5-fold in apoAI-Tg mice. Addition of CA to the HF diet lowered HDL lev els by 1.6-fold in NTg and 2.5-fold in apoAI-Tg mice. Transfection studies with the apoA-I promoter suggested the presence of a putative cis-acting el ement responsible for the CA-mediated down-regulation of the apoA-I promote r activity. Measurements of apoA-I regulatory protein-1 (ARP-1) mRNA, a neg ative regulator of the apoA-I gene in the mouse liver showed that CA increa sed the ARP-1 mRNA levels. Because apoA-I gene transcription alone was not sufficient to account for the lowering of plasma HDL levels, scavenger rece ptor-B1 (SR-B1) and hepatic lipase (HL) mRNAs levels were quantitated. The levels of SR-B1 and HL mRNA were not changed by dietary CA. These studies s uggest that dietary cholate regulates plasma levels of apoA-I primarily by a transcriptional mechanism via a putative bile acid response element invol ving a negative regulator of apoA-I, and partly by an unidentified post-tra nscriptional mechanism.