Abstract
Literature suggests that glucocorticoid (GC) exposure during early life may have long-term consequences into adult life. GCs are known to influence hepatic bile acid synthesis and their transport within the enterohepatic circulation. This study addresses effects of early postnatal exposure to GC on hepatic expression of key genes in bile acid metabolism and bile acid kinetics in adult rats. Male rats were treated with either dexamethasone (DEX) or saline at days 1–3 d after birth. Liver tissue and blood were collected from 2 d to 50 wk of age. Bile acid kinetics were determined at week 8. DEX acutely induced hepatic mRNA levels of cholesterol 7α-hydroxylase (Cyp7a1), cholesterol 27-hydroxylase (Cyp27), and in particular sterol 12α-hydroxylase (Cyp8b1), whereas expression of the bile acid transporters bile salt export pump (Bsep) and sodium taurocholate cotransporting polypeptide (Ntcp) was moderately affected. Neonatal DEX administration led to increased bilary lipid secretion, decreased Cyp8B1 mRNA expression and a 3-fold higher Cyp7a1/Cyp8b1 mRNA ratio in rats at week 8 compared with age-matched controls without alterations in bile acid kinetics. Therefore, neonatal DEX administration causes altered gene expressions later in life that are not translated into quantitative changes in bile acid kinetics.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- Abcg5:
-
ATP-binding cassette, sub-family G (WHITE), member 5
- Bsep:
-
bile salt export pump Abcb11
- CA:
-
cholic acid
- CDCA:
-
Chenodeoxycholic acid
- Cyp7a1:
-
cytochrome P450, 7a1 (cholesterol alpha-7-hydroxylase)
- Cyp8b1:
-
cytochrome P450, 8b1, sterol 12 alpha-hydrolase
- DEX:
-
dexamethasone
- Fic-1:
-
aminophospholipid translocase Atp8b
- Fxr:
-
farnesoid X receptor
- GC:
-
Glucocorticoids
- Hmgr:
-
HMG-CoA reductase
- Hnf4α:
-
hepatic nuclear factor 4α, Nr2a1
- Lxrα:
-
liver X receptor α
- Mdr2:
-
multidrug resistance protein 2
- Mrp2:
-
multidrug resistance-related protein 2
- Ntcp:
-
Na/taurocholate cotransporting polypeptide 1
- SAL:
-
saline
- Shp:
-
small heterodimer partner
References
Hofmann AF 1999 Bile acids: the good, the bad, and the ugly. News Physiol Sci 14: 24–29
Redinger RN 2003 Nuclear receptors in cholesterol catabolism: molecular biology of the enterohepatic circulation of bile salts and its role in cholesterol homeostasis. J Lab Clin Med 142: 7–20
Claudel T, Staels B, Kuipers F 2005 The Farnesoid X receptor: a molecular link between bile acid and lipid and glucose metabolism. Arterioscler Thromb Vasc Biol 25: 2020–2030
Castro J, Amigo L, Miquel JF, Gälman C, Crovari F, Raddatz A, Zanlungo S, Jalil R, Rudling M, Nervi F 2007 Increased activity of hepatic microsomal triglyceride transfer protein and bile acid synthesis in gallstone disease. Hepatology 45: 1261–1266
Duane WC 1995 Abnormal bile acid absorption in familial hypertriglyceridemia. J Lipid Res 36: 96–107
Angelin B, Hershon KS, Brunzell JD 1987 Bile acid metabolism in hereditary forms of hypertriglyceridemia: evidence for an increased synthesis rate in monogenic familial hypertriglyceridemia. Proc Natl Acad Sci USA 84: 5434–5438
Yeh TF, Lin YJ, Hsieh WS, Lin HC, Lin CH, Chen JY, Kao HA, Chien CH 1997 Early postnatal dexamethasone therapy for the prevention of chronic lung disease in preterm infants with respiratory distress syndrome: a multicenter clinical trial. Pediatrics 100: E3
Halliday HL 2001 The effect of postnatal steroids on growth and development. J Perinat Med 29: 281–285
Bal MP, de Vries WB, van der Leij FR, van Oosterhout MF, Baan J, van der Wall EE, van Bel F, Steendijk P 2005 Left ventricular pressure-volume relationships during normal growth and development in the adult rat—studies in 8- and 50-week-old male Wistar rats. Acta Physiol Scand 185: 181–191
Simon FR, Fortune J, Iwahashi M, Qadri I, Sutherland E 2004 Multihormonal regulation of hepatic sinusoidal Ntcp gene expression. Am J Physiol Gastrointest Liver Physiol 287: G782–G794
Stravitz RT, Hylemon PB, Heuman DM, Hagey LR, Schteingart CD, Ton-Nu HT, Hofmann AF, Vlahcevic ZR 1993 Transcriptional regulation of cholesterol 7 alpha-hydroxylase mRNA by conjugated bile acids in primary cultures of rat hepatocytes. J Biol Chem 268: 13987–13993
Stravitz RT, Vlahcevic ZR, Russell TL, Heizer ML, Avadhani NG, Hylemon PB 1996 Regulation of sterol 27-hydroxylase and an alternative pathway of bile acid biosynthesis in primary cultures of rat hepatocytes. J Steroid Biochem Mol Biol 57: 337–347
Watkins JB, Szczepanik P, Gould JB, Klein P, Lester R 1975 Bile salt metabolism in the human premature infant. Preliminary observations of pool size and synthesis rate following prenatal administration of dexamethasone and phenobarbital. Gastroenterology 69: 706–713
Mashige F, Imai K, Osuga T 1976 A simple and sensitive assay of total serum bile acids. Clin Chim Acta 70: 79–86
Hulzebos CV, Renfurm L, Bandsma RH, Verkade HJ, Boer T, Boverhof R, Tanaka H, Mierau I, Sauer PJ, Kuipers F, Stellaard F 2001 Measurement of parameters of cholic acid kinetics in plasma using a microscale stable isotope dilution technique: application to rodents and humans. J Lipid Res 42: 1923–1929
Voshol PJ, Havinga R, Wolters H, Ottenhoff R, Princen HM, Oude Elferink RP, Groen AK, Kuipers F 1998 Reduced plasma cholesterol and increased fecal sterol loss in multidrug resistance gene 2 P-glycoprotein-deficient mice. Gastroenterology 114: 1024–1034
Bloks VW, Plosch T, van Goor H, Roelofsen H, Baller J, Havinga R, Verkade HJ, van Tol A, Jansen PL, Kuipers F 2001 Hyperlipidemia and atherosclerosis associated with liver disease in ferrochelatase-deficient mice. J Lipid Res 42: 41–50
Grefhorst A, Elzinga BM, Voshol PJ, Plosch T, Kok T, Bloks VW, van der Sluijs FH, Havekes LM, Romijn JA, Verkade HJ, Kuipers F 2002 Stimulation of lipogenesis by pharmacological activation of the liver X receptor leads to production of large, triglyceride-rich very low density lipoprotein particles. J Biol Chem 277: 34182–34190
Hulzebos CV, Wolters H, Plosch T, Kramer W, Stengelin S, Stellaard F, Sauer PJ, Verkade HJ, Kuipers F 2003 Cyclosporin a and enterohepatic circulation of bile salts in rats: decreased cholate synthesis but increased intestinal reabsorption. J Pharmacol Exp Ther 304: 356–363
Plosch T, Kok T, Bloks VW, Smit MJ, Havinga R, Chimini G, Groen AK, Kuipers F 2002 Increased hepatobiliary and fecal cholesterol excretion upon activation of the liver X receptor is independent of ABCA1. J Biol Chem 277: 33870–33877
Kok T, Hulzebos CV, Wolters H, Havinga R, Agellon LB, Stellaard F, Shan B, Schwarz M, Kuipers F 2003 Enterohepatic circulation of bile salts in farnesoid X receptor-deficient mice: efficient intestinal bile salt absorption in the absence of ileal bile acid-binding protein. J Biol Chem 278: 41930–41937
Chiang JY 2004 Regulation of bile acid synthesis: pathways, nuclear receptors, and mechanisms. J Hepatol 40: 539–551
Yu C, Wang F, Kan M, Jin C, Jones RB, Weinstein M, Deng CX, McKeehan WL 2000 Elevated cholesterol metabolism and bile acid synthesis in mice lacking membrane tyrosine kinase receptor FGFR4. J Biol Chem 275: 15482–15489
Ito S, Fujimori T, Furuya A, Satoh J, Nabeshima Y, Nabeshima Y 2005 Impaired negative feedback suppression of bile acid synthesis in mice lacking betaKlotho. J Clin Invest 115: 2202–2208
Nyirenda MJ, Dean S, Lyons V, Chapman KE, Seckl JR 2006 Prenatal programming of hepatocyte nuclear factor 4alpha in the rat: a key mechanism in the ‘foetal origins of hyperglycaemia'?. Diabetologia 49: 1412–1420
Crestani M, De FE, Caruso D, Mitro N, Gilardi F, Vigil Chacon AB, Patelli R, Godio C, Galli G 2004 LXR (liver X receptor) and HNF-4 (hepatocyte nuclear factor-4): key regulators in reverse cholesterol transport. Biochem Soc Trans 32: 92–96
Princen HM, Meijer P, Hofstee B 1989 Dexamethasone regulates bile acid synthesis in monolayer cultures of rat hepatocytes by induction of cholesterol 7 alpha-hydroxylase. Biochem J 262: 341–348
Ellis E, Goodwin B, Abrahamsson A, Liddle C, Mode A, Rudling M, Bjorkhem I, Einarsson C 1998 Bile acid synthesis in primary cultures of rat and human hepatocytes. Hepatology 27: 615–620
Pandak WM, Heuman DM, Redford K, Stravitz RT, Chiang JY, Hylemon PB, Vlahcevic ZR 1997 Hormonal regulation of cholesterol 7alpha-hydroxylase specific activity, mRNA levels, and transcriptional activity in vivo in the rat. J Lipid Res 38: 2483–2491
Trauner M, Boyer JL 2003 Bile salt transporters: molecular characterization, function, and regulation. Physiol Rev 83: 633–671
Turncliff RZ, Meier PJ, Brouwer KL 2004 Effect of dexamethasone treatment on the expression and function of transport proteins in sandwich-cultured rat hepatocytes. Drug Metab Dispos 32: 834–839
Oyadomari S, Matsuno F, Chowdhury S, Kimura T, Iwase K, Araki E, Shichiri M, Mori M, Takiguchi M 2000 The gene for hepatocyte nuclear factor (HNF)-4alpha is activated by glucocorticoids and glucagon, and repressed by insulin in rat liver. FEBS Lett 478: 141–146
Acknowledgements
We thank Fjodor van der Sluijs for the primer design and Theo Boer for the mass spectrometry analyses.
Author information
Authors and Affiliations
Corresponding author
Additional information
Supported by the Graduate School Groningen University Institute for Drug exploration (GUIDE).
Rights and permissions
About this article
Cite this article
Liu, Y., Havinga, R., van der Leij, F. et al. Dexamethasone Exposure of Neonatal Rats Modulates Biliary Lipid Secretion and Hepatic Expression of Genes Controlling Bile Acid Metabolism in Adulthood Without Interfering With Primary Bile Acid Kinetics. Pediatr Res 63, 375–381 (2008). https://doi.org/10.1203/PDR.0b013e318165b8af
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/PDR.0b013e318165b8af
