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Age‐related changes in bile acid synthesis and hepatic nuclear receptor expression

2007; Wiley; Volume: 37; Issue: 6 Linguagem: Inglês

10.1111/j.1365-2362.2007.01808.x

1365-2362

Marco Bertolotti, Chiara Gabbi, Claudia Anzivino, Maurizio Crestani, Nico Mitro, Marina Del Puppo, Cristina Godio, Emma De Fabiani, Daria Macchioni, Lucia Carulli, Antônio Rossi, Matteo Ricchi, Paola Loria, Nicola Carulli,

Liver Disease Diagnosis and Treatment

Abstract Background Recent data highlighted the role of nuclear receptors in the transcriptional regulation of the limiting enzyme of bile acid synthesis, cholesterol 7α‐hydroxylase, in cellular and animal models. This study was designed to analyze the effects of age on cholesterol 7α‐hydroxylase and related nuclear receptor expression in human livers. Design Surgical liver biopsies were obtained in 23 patients requiring operation on the gastrointestinal tract. mRNA levels of cholesterol 7α‐hydroxylase and related nuclear receptors and co‐activators were assayed by quantitative real‐time RT‐PCR. Serum levels of 7α‐hydroxy‐4‐cholesten‐3‐one, a marker of bile acid synthesis, were assayed by gas‐liquid chromatography:mass spectrometry. Results Ageing was inversely correlated with serum 7α‐hydroxy‐4‐cholesten‐3‐one and with cholesterol 7α‐hydroxylase mRNA levels ( r = –0·44 and r = −0·45 on a semi‐log scale, respectively, P < 0·05). Among different nuclear factors, 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 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 7α‐hydroxylase expression. No suppressive effect of short heterodimer partner expression on cholesterol 7α‐hydroxylase was observed. Conclusions Ageing associates with reduced bile acid synthesis, possibly related to decreased hepatic expression of hepatocyte nuclear factor‐4 and consequently of cholesterol 7α‐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.