Abstract
Recent data highlighted the role of nuclear receptors in the transcriptional regulation of the limiting enzyme of bile acid synthesis, cholesterol 7alpha-hydroxylase, in cellular and animal models. This study was designed to analyze the effects of age on cholesterol 7alpha-hydroxylase and related nuclear receptor expression in human livers. Surgical liver biopsies were obtained in 23 patients requiring operation on the gastrointestinal tract. mRNA levels of cholesterol 7alpha-hydroxylase and related nuclear receptors and co-activators were assayed by quantitative real-time RT-PCR. Serum levels of 7alpha-hydroxy-4-cholesten-3-one, a marker of bile acid synthesis, were assayed by gas-liquid chromatography:mass spectrometry. Ageing was inversely correlated with serum 7alpha-hydroxy-4-cholesten-3-one and with cholesterol 7alpha-hydroxylase mRNA levels (r = -0.44 and r = -0.45 on a semi-log scale, respectively, P < 0.05). Among different nuclear factors, cholesterol 7alpha-hydroxylase mRNA best correlated with hepatocyte nuclear factor-4 (r = 0.55 on a log scale, P < 0.05); hepatocyte nuclear factor-4 levels were also inversely correlated with age (r = -0.64 on a semi-log scale, P < 0.05). Age was inversely correlated with serum insulin-like growth factor-I levels, which were directly correlated with hepatocyte nuclear factor-4 and cholesterol 7alpha-hydroxylase expression. No suppressive effect of short heterodimer partner expression on cholesterol 7alpha-hydroxylase was observed. Ageing associates with reduced bile acid synthesis, possibly related to decreased hepatic expression of hepatocyte nuclear factor-4 and consequently of cholesterol 7alpha-hydroxylase. Age-related modifications of the growth hormone/insulin-like growth factor axis might play a role. These findings may help to elucidate the pathophysiology of age-related modifications of cholesterol metabolism.
Highlights
Hepatic degradation to bile acids is the most relevant metabolic pathway whereby the organism can dispose of excess cholesterol [1,2]
Cholesterol 7α-hydroxylase mRNA best correlated with hepatocyte nuclear factor-4 (r = 0·55 on a log scale, P < 0·05); hepatocyte nuclear factor-4 levels were inversely correlated with age (r = –0·64 on a semi-log scale, P < 0·05)
Age was inversely correlated with serum insulin-like growth factor-I levels, which were directly correlated with hepatocyte nuclear factor-4 and cholesterol 7α-hydroxylase expression
Summary
Hepatic degradation to bile acids is the most relevant metabolic pathway whereby the organism can dispose of excess cholesterol [1,2]. Recent evidence highlighted the role of nuclear receptors in the transcriptional control of CYP7A1 [4,5,6] suggesting a cascade mechanism of control where the interaction of hydrophobic bile acids with farnesoid X receptor (FXR), identified as the bile acid receptor, triggers overexpression of the co-repressor short heterodimer partner (SHP) leading in turn to down-regulation of CYP7A1 gene transcription [7,8]. This mechanism involves a negative interaction with the co-activator CYP7A1 promoter binding factor/liver receptor homologue-1 (CPF/LRH-1). This study was designed to analyze the effects of age on cholesterol 7α-hydroxylase and related nuclear receptor expression in human livers
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