title: Age-related changes in bile acid synthesis and hepatic nuclear receptor expression.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine, Endocrinology, Metabolism and Geriatrics, University of Modena and Reggio Emilia, Modena, Italy. bertolotti.marco@unimore.it
authors.forename: M
authors.initials: M
authors.lastname: Bertolotti
authors.forename: C
authors.initials: C
authors.lastname: Gabbi
authors.forename: C
authors.initials: C
authors.lastname: Anzivino
authors.forename: M
authors.initials: M
authors.lastname: Crestani
authors.forename: N
authors.initials: N
authors.lastname: Mitro
authors.forename: M
authors.initials: M
authors.lastname: Del Puppo
authors.forename: C
authors.initials: C
authors.lastname: Godio
authors.forename: E
authors.initials: E
authors.lastname: De Fabiani
authors.forename: D
authors.initials: D
authors.lastname: Macchioni
authors.forename: L
authors.initials: L
authors.lastname: Carulli
authors.forename: A
authors.initials: A
authors.lastname: Rossi
authors.forename: M
authors.initials: M
authors.lastname: Ricchi
authors.forename: P
authors.initials: P
authors.lastname: Loria
authors.forename: N
authors.initials: N
authors.lastname: Carulli
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism*; D005260:Female; D051557:Hepatocyte Nuclear Factor 4 / Q000032:analysis / Q000235:genetics*; D006801:Humans; D050155:Lipogenesis; D008099:Liver / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D018160:Receptors, Cytoplasmic and Nuclear
chemical_list: D001647:Bile Acids and Salts; D051557:Hepatocyte Nuclear Factor 4; D018160:Receptors, Cytoplasmic and Nuclear; D002790:Cholesterol 7-alpha-Hydroxylase