Influence of age on bile acid synthesis: Role of hepatic expression of nuclear receptors

Bile acid synthesis plays a key role in cholesterol homeostasis. Recent data have highlighted the role of nuclear receptors in the transcriptional regulation of the limiting enzyme, cholesterol 7alpha-hydroxylase (CYP7A1), in cellular and animal models. AIM of the present study was to analyze the effects of age on the expression of CYP7A1 and related nuclear receptors in human livers. METHODS. Liver biopsies were obtained in 22 untreated patients with abdominal diseases requiring surgery. mRNA levels of CYP7A1 and related nuclear receptors and coactivators were assayed by quantitative real-time RT-PCR. Serum levels of 7alpha-hydroxycholest-3-one (3-ONE), a marker of bile acid synthesis, were assayed by GC-MS. RESULTS. Aging was inversely correlated with serum 3-ONE and with CYP7A1 mRNA levels (r = -0.53 and r = -0.48, respectively, p < 0.05). Among the different nuclear factors, CYP7A1 mRNA best correlated with HNF-4 (r = 0.51, p < 0.05); HNF-4 levels were inversely correlated with age (r = -0.72, p < 0.05). Age was inversely correlated with serum IGF-1 levels which, in turn, were directly correlated with HNF-4 expression. CONCLUSIONS. Aging associates with reduced bile acid synthesis, in agreement with previous evidence from this laboratory; this might be related with reduced expression of hepatic nuclear receptors, in particular HNF-4, in turn leading to reduced expression of CYP7A1. Age-related modifications of the GH/IGF axis might play a role. The changes observed may help to understand age-related modifications of cholesterol metabolism.