Original articles
Daniel Rizzolo, Bo Kong, Rulaiha E. Taylor, Anita Brinker, Michael Goedken, Brian Buckley, Grace L. Guo. Bile acid homeostasis in female mice deficient in Cyp7a1 and Cyp27a1[J]. Acta Pharmaceutica Sinica B, 2021, 11(12): 3847-3856

Bile acid homeostasis in female mice deficient in Cyp7a1 and Cyp27a1
Daniel Rizzoloa,b,d, Bo Konga, Rulaiha E. Taylora, Anita Brinkerb, Michael Goedkenc, Brian Buckleya,b, Grace L. Guoa,b,d,e
a. Department of Pharmacology and Toxicology, School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA;
b. Environmental and Occupational Health Institute, Rutgers University, Piscataway, NJ 08854, USA;
c. Office of Research and Economic Development, Research Pathology Services, Rutgers University, Piscataway, NJ 08854, USA;
d. Rutgers Center of Lipid Research, Rutgers University, New Brunswick, NJ 08901, USA;
e. Department of Veterans Affairs New Jersey Health Care System, East Orange, NJ 07018, USA
Bile acids (BAs) are amphipathic molecules important for metabolism of cholesterol, absorption of lipids and lipid soluble vitamins, bile flow, and regulation of gut microbiome. There are over 30 different BA species known to exist in humans and mice, which are endogenous modulators of at least 6 different membrane or nuclear receptors. This diversity of ligands and receptors play important roles in health and disease; however, the full functions of each individual BA in vivo remain unclear. We generated a mouse model lacking the initiating enzymes, CYP7A1 and CYP27A1, in the two main pathways of BA synthesis. Because females are more susceptible to BA related diseases, such as intrahepatic cholestasis of pregnancy, we expanded this model into female mice. The null mice of Cyp7a1 and Cyp27a1 were crossbred to create double knockout (DKO) mice. BA concentrations in female DKO mice had reductions in serum (63%), liver (83%), gallbladder (94%), and small intestine (85%), as compared to WT mice. Despite low BA levels, DKO mice had a similar expression pattern to that of WT mice for genes involved in BA regulation, synthesis, conjugation, and transport. Additionally, through treatment with a synthetic FXR agonist, GW4064, female DKO mice responded to FXR activation similarly to WT mice.
Key words:    Bile acids    Farnesoid X receptor    Female    Fibroblast growth factor 15    CYP7A1    CYP27A1   
Received: 2020-12-28     Revised: 2021-04-13
DOI: 10.1016/j.apsb.2021.05.023
Funds: This work was supported by the National Institutes of Health (NIH-R01GM104037; NIH-R21ES029258; NIH-T32ES007148;VA-BX002741;NIH-F31DK122725; RCLR graduate student award fund, USA). Graphical abstract created with BioRender.com.
Corresponding author: Grace L. Guo,E-mail:glg48@eohsi.rutgers.edu     Email:glg48@eohsi.rutgers.edu
Author description:
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Daniel Rizzolo
Bo Kong
Rulaiha E. Taylor
Anita Brinker
Michael Goedken
Brian Buckley
Grace L. Guo

[1] Li T, Chiang JY. Bile acid signaling in metabolic disease and drug therapy. Pharmacol Rev 2014;66:948-983
[2] Wong MH, Oelkers P, Craddock AL, Dawson PA. Expression cloning and characterization of the hamster ileal sodium-dependent bile acid transporter. J Biol Chem 1994;269:1340-1347
[3] Dawson PA, Hubbert M, Haywood J, Craddock AL, Zerangue N, Christian WV, et al. The heteromeric organic solute transporter alpha-beta, Ostalpha-Ostbeta, is an ileal basolateral bile acid transporter. J Biol Chem 2005;280:6960-6968
[4] Hagenbuch B, Meier PJ. Molecular cloning, chromosomal localization, and functional characterization of a human liver Na+/bile acid cotransporter. J Clin Invest 1994;93:1326-1331
[5] Jacquemin E, Hagenbuch B, Stieger B, Wolkoff AW, Meier PJ. Expression cloning of a rat liver Na+-independent organic anion transporter. Proc Natl Acad Sci U S A 1994;91:133-137
[6] Chiang JY. Bile acid metabolism and signaling. Compr Physiol 2013;3:1191-1212
[7] Takahashi S, Fukami T, Masuo Y, Brocker CN, Xie C, Krausz KW, et al. Cyp2c70 is responsible for the species difference in bile acid metabolism between mice and humans. J Lipid Res 2016;57:2130-2137
[8] Ridlon JM, Kang DJ, Hylemon PB, Bajaj JS. Bile acids and the gut microbiome. Curr Opin Gastroenterol 2014;30:332-338
[9] Makishima M, Okamoto AY, Repa JJ, Tu H, Learned RM, Luk A, et al. Identification of a nuclear receptor for bile acids. Science 1999;284:1362
[10] Staudinger JL, Goodwin B, Jones SA, Hawkins-Brown D, MacKenzie KI, LaTour A, et al. The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. Proc Natl Acad Sci U S A 2001;98:3369-3374
[11] Xie W, Radominska-Pandya A, Shi Y, Simon CM, Nelson MC, Ong ES, et al. An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids. Proc Natl Acad Sci U S A 2001;98:3375-3380
[12] Makishima M, Lu TT, Xie W, Whitfield GK, Domoto H, Evans RM, et al. Vitamin D receptor as an intestinal bile acid sensor. Science 2002;296:1313-1316
[13] Kawamata Y, Fujii R, Hosoya M, Harada M, Yoshida H, Miwa M, et al. A G protein-coupled receptor responsive to bile acids. J Biol Chem 2003;278:9435-9440
[14] Maruyama T, Miyamoto Y, Nakamura T, Tamai Y, Okada H, Sugiyama E, et al. Identification of membrane-type receptor for bile acids (M-BAR). Biochem Biophys Res Commun 2002;298:714-719
[15] Studer E, Zhou X, Zhao R, Wang Y, Takabe K, Nagahashi M, et al. Conjugated bile acids activate the sphingosine-1-phosphate receptor 2 in primary rodent hepatocytes. Hepatology (Baltimore) 2012;55:267-276
[16] Sheikh Abdul Kadir SH, Miragoli M, Abu-Hayyeh S, Moshkov AV, Xie Q, Keitel V, et al. Bile acid-induced arrhythmia is mediated by muscarinic M2 receptors in neonatal rat cardiomyocytes. PLoS One 2010;5:e9689
[17] Hofmann AF. Bile acids: trying to understand their chemistry and biology with the hope of helping patients. Hepatology (Baltimore) 2009;49:1403-1418
[18] Han J, Liu Y, Wang R, Yang J, Ling V, Borchers CH. Metabolic profiling of bile acids in human and mouse blood by LC-MS/MS in combination with phospholipid-depletion solid-phase extraction. Anal Chem 2015;87:1127-1136
[19] Rizzolo D, Buckley K, Kong B, Zhan L, Shen J, Stofan M, et al. Bile acid homeostasis in a cholesterol 7α-hydroxylase and sterol 27-hydroxylase double knockout mouse model. Hepatology (Baltimore) 2019;70:389-402
[20] You S, Cui AM, Hashmi SF, Zhang X, Nadolny C, Chen Y, et al. Dysregulation of bile acids increases the risk for preterm birth in pregnant women. Nat Commun 2020;11:2111
[21] Lee RH, Goodwin TM, Greenspoon J, Incerpi M. The prevalence of intrahepatic cholestasis of pregnancy in a primarily Latina Los Angeles population. J Perinatol 2006;26:527-532
[22] Floreani A, Gervasi MT. New insights on intrahepatic cholestasis of pregnancy. Clin Liver Dis 2016;20:177-189
[23] Pusl T, Beuers U. Intrahepatic cholestasis of pregnancy. Orphanet J Rare Dis 2007;2:26
[24] Chen J, Zhao KN, Liu GB. Estrogen-induced cholestasis: pathogenesis and therapeutic implications. Hepatogastroenterology 2013;60:1289-1296
[25] Everson GT, McKinley C, Kern F Jr. Mechanisms of gallstone formation in women. Effects of exogenous estrogen (Premarin) and dietary cholesterol on hepatic lipid metabolism. J Clin Invest 1991;87:237-246
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