Of mice and men: murine bile acids explain species differences in the regulation of bile acid and cholesterol metabolism

Abstract

Compared with humans, rodents have higher synthesis of cholesterol and bile acids (BAs) and faster clearance and lower levels of serum LDL-cholesterol. Paradoxically, they increase BA synthesis in response to bile duct ligation (BDL). Another difference is the production of hydrophilic 6-hydroxylated muricholic acids (MCAs), which may antagonize the activation of FXRs, in rodents versus humans. We hypothesized that the presence of MCAs is key for many of these metabolic differences between mice and humans. We thus studied the effects of genetic deletion of the Cyp2c70 gene, previously proposed to control MCA formation. Compared with WT animals, KO mice created using the CRISPR/Cas9 system completely lacked MCAs, and displayed >50% reductions in BA and cholesterol synthesis and hepatic LDL receptors, leading to a marked increase in serum LDL-cholesterol. The doubling of BA synthesis following BDL in WT animals was abolished in KO mice, despite extinguished intestinal fibroblast growth factor (Fgf)15 expression in both groups. Accumulation of cholesterol-enriched particles (“Lp-X”) in serum was almost eliminated in KO mice. Livers of KO mice were increased 18% in weight, and serum markers of liver function indicated liver damage. The human-like phenotype of BA metabolism in KO mice could not be fully explained by the activation of FXR-mediated changes. In conclusion, the presence of MCAs is critical for many of the known metabolic differences between mice and humans. The Cyp2c70-KO mouse should be useful in studies exploring potential therapeutic targets for human disease. Compared with humans, rodents have higher synthesis of cholesterol and bile acids (BAs) and faster clearance and lower levels of serum LDL-cholesterol. Paradoxically, they increase BA synthesis in response to bile duct ligation (BDL). Another difference is the production of hydrophilic 6-hydroxylated muricholic acids (MCAs), which may antagonize the activation of FXRs, in rodents versus humans. We hypothesized that the presence of MCAs is key for many of these metabolic differences between mice and humans. We thus studied the effects of genetic deletion of the Cyp2c70 gene, previously proposed to control MCA formation. Compared with WT animals, KO mice created using the CRISPR/Cas9 system completely lacked MCAs, and displayed >50% reductions in BA and cholesterol synthesis and hepatic LDL receptors, leading to a marked increase in serum LDL-cholesterol. The doubling of BA synthesis following BDL in WT animals was abolished in KO mice, despite extinguished intestinal fibroblast growth factor (Fgf)15 expression in both groups. Accumulation of cholesterol-enriched particles (“Lp-X”) in serum was almost eliminated in KO mice. Livers of KO mice were increased 18% in weight, and serum markers of liver function indicated liver damage. The human-like phenotype of BA metabolism in KO mice could not be fully explained by the activation of FXR-mediated changes. In conclusion, the presence of MCAs is critical for many of the known metabolic differences between mice and humans. The Cyp2c70-KO mouse should be useful in studies exploring potential therapeutic targets for human disease. Bile acids (BAs) are amphiphilic molecules synthesized from cholesterol in the liver, stored in the gallbladder, and released into the gut after food intake. By solubilizing lipophilic molecules, they promote biliary lipid secretion and intestinal fat absorption. Through their subsequent active uptake in the distal ileum and reuptake by the liver, the pool size of BAs is conserved. The rate of formation of BAs from cholesterol in the liver is modulated by the flux of BAs through this enterohepatic circulation by regulation of the rate-limiting enzyme, cholesterol 7α-hydroxylase (CYP7A1). The recognition that BAs may also act as signaling molecules in overall regulation of body metabolism has enhanced the interest for how modulation of their metabolism may be used therapeutically for treatment of fatty liver disease, dyslipidemia, and type 2 diabetes (1Bertaggia E. Jensen K.K. Castro-Perez J. Xu Y. Di Paolo G. Chan R.B. Wang L. Haeusler R.A. Cyp8b1 ablation prevents Western diet-induced weight gain and hepatic steatosis because of impaired fat absorption.Am. J. Physiol. Endocrinol. Metab. 2017; 313: E121-E133Crossref PubMed Scopus (41) Google Scholar, 2de Aguiar Vallim T.Q. Tarling E.J. Edwards P.A. Pleiotropic roles of bile acids in metabolism.Cell Metab. 2013; 17: 657-669Abstract Full Text Full Text PDF PubMed Scopus (473) Google Scholar, 3Lefebvre P. Cariou B. Lien F. Kuipers F. Staels B. Role of bile acids and bile acid receptors in metabolic regulation.Physiol. Rev. 2009; 89: 147-191Crossref PubMed Scopus (1026) Google Scholar, 4Li T. Chiang J.Y. Bile acid signaling in metabolic disease and drug therapy.Pharmacol. Rev. 2014; 66: 948-983Crossref PubMed Scopus (405) Google Scholar). A large part of our knowledge regarding cholesterol and BA metabolism emerges from studies in rats and mice. However, there are major known species differences limiting the translation of such data to human physiology. Compared with humans, the basal turnover of BAs and cholesterol, as well as that of circulating LDL, is higher and the concentration of LDL-cholesterol much lower in mice (5Gälman C. Arvidsson I. Angelin B. Rudling M. Monitoring hepatic cholesterol 7{alpha}-hydroxylase activity by assay of the stable bile acid intermediate 7{alpha}-hydroxy-4-cholesten-3-one in peripheral blood.J. Lipid Res. 2003; 44: 859-866Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar, 6Li J. Dawson P.A. Animal models to study bile acid metabolism.Biochim. Biophys. Acta Mol. Basis Dis. 2019; 1865: 895-911Crossref PubMed Scopus (41) Google Scholar). On the other hand, interruption of the enterohepatic circulation of BAs seems to elicit stronger effects on cholesterol metabolism and LDL levels in humans (7Al-Khaifi C. Angelin B. Rudling M. of circulating and bile acids in the modulation of human PubMed Scopus Google Scholar). on their BAs have on biliary lipid intestinal fat and of BA the to through their with the in the distal ileum and in the liver J. Dawson P.A. Animal models to study bile acid metabolism.Biochim. Biophys. Acta Mol. Basis Dis. 2019; 1865: 895-911Crossref PubMed Scopus (41) Google Scholar). In to humans, of the BA pool in mice of 6-hydroxylated muricholic acids J. Dawson P.A. Animal models to study bile acid metabolism.Biochim. Biophys. Acta Mol. Basis Dis. 2019; 1865: 895-911Crossref PubMed Scopus (41) Google Scholar). The of these hydrophilic BAs is their the intestinal of cholesterol and fat (1Bertaggia E. Jensen K.K. Castro-Perez J. Xu Y. Di Paolo G. Chan R.B. Wang L. Haeusler R.A. Cyp8b1 ablation prevents Western diet-induced weight gain and hepatic steatosis because of impaired fat absorption.Am. J. Physiol. Endocrinol. Metab. 2017; 313: E121-E133Crossref PubMed Scopus (41) Google Scholar, Y. G. Rudling M. in muricholic bile acids to weight and to impaired PubMed Scopus Google Scholar, P. of Cyp8b1 by PubMed Scopus Google Scholar, C. P. Wang J. I. G. M. acid as key of cholesterol intestinal and hepatic in Biophys. PubMed Scopus Google Scholar). The presence of MCAs may also the by such as acid acid and acid J. Dawson P.A. Animal models to study bile acid metabolism.Biochim. Biophys. Acta Mol. Basis Dis. 2019; 1865: 895-911Crossref PubMed Scopus (41) Google Scholar). The that MCAs J. Angelin B. T. M. F. bile acid metabolism by the levels of a Metab. 2013; 17: Full Text Full Text PDF PubMed Scopus Google may that their the basal synthesis of BAs and cholesterol in mice with humans (5Gälman C. Arvidsson I. Angelin B. Rudling M. Monitoring hepatic cholesterol 7{alpha}-hydroxylase activity by assay of the stable bile acid intermediate 7{alpha}-hydroxy-4-cholesten-3-one in peripheral blood.J. Lipid Res. 2003; 44: 859-866Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar, 6Li J. Dawson P.A. Animal models to study bile acid metabolism.Biochim. Biophys. Acta Mol. Basis Dis. 2019; 1865: 895-911Crossref PubMed Scopus (41) Google Scholar, M. mouse bile acid to mice and rats bile Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, M. Y. of bile acid the bile acid pool and bile acids with Dis. PubMed Scopus Google Scholar). Another major difference between rodents and humans the of on BA bile duct ligation BA synthesis by in mice and rats J. R.A. of cholesterol and bile acid in J. PubMed Scopus Google Scholar, J. of biliary on of in bile acid Lipid Res. Full Text PDF PubMed Google Scholar, T. M. L. G. B. growth factor as enterohepatic to bile acid Metab. Full Text Full Text PDF PubMed Scopus Google in humans is with BA synthesis J. M. Rudling M. Angelin B. G. B. E. of bile acid metabolism in biliary of by and to Scopus Google Scholar, and is increased in human Bile and targets of bile acid Scholar, expression of the bile fibroblast growth factor in the liver of with 2009; PubMed Scopus Google Scholar). response in rodents following BDL has explained as a of the secretion of fibroblast growth factor from the ileum in this T. M. L. G. B. growth factor as enterohepatic to bile acid Metab. Full Text Full Text PDF PubMed Scopus Google with the of a of BA synthesis by BA flux B. Rudling M. fibroblast growth as metabolic critical Metab. Full Text Full Text PDF PubMed Scopus Google Scholar, M. M. M. M. of bile acid synthesis enterohepatic circulation in PubMed Scopus Google Scholar, Chiang J.Y. E.J. of cholesterol and activity by and cholesterol in the biliary Full Text PDF PubMed Google Scholar). In human the hepatic expression of is leading to higher circulating J. M. Rudling M. Angelin B. G. B. E. of bile acid metabolism in biliary of by and to Scopus Google Scholar, and is increased in human Bile and targets of bile acid Scholar, expression of the bile fibroblast growth factor in the liver of with 2009; PubMed Scopus Google hepatic in mice expression of the bile fibroblast growth factor in the liver of with 2009; PubMed Scopus Google Scholar). that may be proposed for the increase in BA production following BDL in rodents J. R.A. of cholesterol and bile acid in J. PubMed Scopus Google Scholar, Y. J.Y. of bile duct ligation on bile acid in mouse serum and PubMed Scopus Google could be that to the of hydrophilic MCAs known to in this M. mouse bile acid to mice and rats bile Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, M. Y. of bile acid the bile acid pool and bile acids with Dis. PubMed Scopus Google Scholar). in mice with deletion of the indicated that the Cyp2c70 may be for the for MCA production in the mouse T. Y. C. Cyp2c70 is for the species difference in bile acid metabolism between mice and Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). on this mice in this to that Cyp2c70-KO mice MCAs as that BA and cholesterol as well as hepatic LDL receptors, are and serum LDL levels increased in such and that the of BA synthesis following BDL is abolished in Cyp2c70-KO mice. that a of differences in BA and cholesterol metabolism between mice and humans are on The human-like metabolic phenotype of Cyp2c70-KO mice also that this may a useful in studies on for human disease. Cyp2c70-KO mice were and by was used to Cyp2c70-KO mice on a of mice. of the mouse Cyp2c70 gene, on mouse was as a The of the Cyp2c70 was The was into to a expression and were by in and into the with were into mice were by and used for were and were from the and by which of was to the and and mice were used for these is in the phenotype of Cyp2c70-KO mice was using of Cyp2c70-KO mice and WT for and were in system in a and a with and and was to the by the for were for with to of WT Cyp2c70-KO mice for and were to BDL as E. F. Bile duct ligation in of liver and by PubMed Scopus Google Scholar). mice were by and BDL was after The bile duct was in and was not between the to the of bile were for ligation of the bile were to and to a with to and food after and were the Animal a to The is for and of Animal and were by the Animal and of and Animal of In were from to for was using the lipid was with and concentration was by was by system using for their are in the and A and were used as The was used to the as activity of hepatic was in liver by as previously (5Gälman C. Arvidsson I. Angelin B. Rudling M. Monitoring hepatic cholesterol 7{alpha}-hydroxylase activity by assay of the stable bile acid intermediate 7{alpha}-hydroxy-4-cholesten-3-one in peripheral blood.J. Lipid Res. 2003; 44: 859-866Abstract Full Text Full Text PDF PubMed Scopus (156) Google using as and were to a liver and for the lower was was and the lower into was for cholesterol in was in the other and the to in a for and were for The was for cholesterol were with of and were in of and using were to using assay were as L. C. Angelin B. Rudling M. of type in the and regulation of liver 2009; PubMed Scopus Google from liver as in the were on to and the LDL by with and by and by a and was using the by with and as were using as P. L. Angelin B. Rudling M. in and with J. PubMed Scopus Google Scholar). for BA production cholesterol synthesis and cholesterol and were as (7Al-Khaifi C. Angelin B. Rudling M. of circulating and bile acids in the modulation of human PubMed Scopus Google Scholar, L. P. E. Angelin B. Rudling M. lower and LDL cholesterol not bile acid synthesis in PubMed Scopus Google Scholar, concentration is of cholesterol synthesis in Lipid Res. Full Text PDF PubMed Google Scholar). BAs in serum and bile were by using of and BAs as (7Al-Khaifi C. Angelin B. Rudling M. of circulating and bile acids in the modulation of human PubMed Scopus Google Scholar). of and and BAs were from liver function serum of and were by from using and intestinal BAs were by using of and BAs as of a in were with of and of BA and for were to and a of following a The was in of and of this were BAs were by as (7Al-Khaifi C. Angelin B. Rudling M. of circulating and bile acids in the modulation of human PubMed Scopus Google Scholar). and were of the and acid were from of and and BAs were from The data are as The of difference was by after were was We to deletion of the Cyp2c70 MCAs by serum BAs by MCAs of the serum BAs in WT mice, KO mice were of MCAs, a on for their formation of the BA of and and The MCA acid and were increased by with differences were for BAs in the liver and BAs in were with serum of the Cyp2c70 in of the MCAs, with of the for MCA and in with the by T. Y. C. Cyp2c70 is for the species difference in bile acid metabolism between mice and Lipid Res. Full Text Full Text PDF PubMed Scopus Google that the Cyp2c70 is for MCA body weight was in the liver weight was 18% higher in KO mice The activity of the rate-limiting in BA cholesterol was by in KO mice A was for hepatic and a was for the serum of BA The hepatic Cyp8b1 was by in KO mice In the KO animals, the of cholesterol to BAs was with increased hepatic and cholesterol by and the hepatic of was not of in cholesterol and were by and was also a for expression of the type of the LDL a by >50% in KO animals In with the of the serum cholesterol was increased by in KO mice to a marked increase in LDL-cholesterol serum were were also increased The serum for body cholesterol synthesis was in KO mice markers for cholesterol and were by in KO mice and in serum and liver in WT and Cyp2c70-KO from weight weight serum cholesterol serum serum BAs liver BAs liver cholesterol liver cholesterol from in a and Cyp8b1 were lower in the of KO animals, the response for other was there was increase in and in the was The expression of to be other and which are targets of were not was and there was a for In to was in the liver, targets of and increased expression in the ileum of KO there was also a for enhanced levels of BA and and were in KO mice the expression of is to be by the flux of this is the of the of MCAs in the enterohepatic The of increased expression versus increased hepatic to BAs for the of hepatic BA synthesis in KO mice could not be from the However, that the BA synthesis in these animals to increased cholesterol in the in the our that the of hydrophilic MCAs following BDL is in the of BA synthesis T. M. L. G. B. growth factor as enterohepatic to bile acid Metab. Full Text Full Text PDF PubMed Scopus Google BDL and WT and KO mice after The differences between WT and KO mice in the could be the of animals body weight by in both BDL liver weight was in WT animals was in KO animals We serum markers of liver function and in this and could that they were increased in KO animals these markers were increased in both WT and KO mice, the levels in the KO of liver was with liver in the KO animals and indicated following BDL in this and lipid in serum and liver of BDL WT and Cyp2c70-KO weight from of versus BDL of from of versus BDL of weight from of versus BDL of serum cholesterol from of versus BDL of from of versus BDL of from of versus BDL of from of versus BDL of from of versus BDL of from of versus BDL of serum from of versus BDL of from of versus BDL of from of versus BDL of from of versus BDL of serum BAs from of versus BDL of liver BAs from of versus BDL of from of versus BDL of liver cholesterol from of versus BDL of from of versus BDL of liver cholesterol from of versus BDL of from of versus BDL of from of versus BDL of from of versus BDL of from of versus BDL of from of versus BDL of in a serum BAs increased in WT mice and in KO mice The BAs and which of serum BAs in WT mice, were eliminated following MCAs and the In with the and of BAs in KO mice BDL in KO mice, the of was not the from to were for BAs in the liver, and bile J. R.A. of cholesterol and bile acid in J. PubMed Scopus Google Scholar, J. of biliary on of in bile acid Lipid Res. Full Text PDF PubMed Google Scholar, T. M. L. G. B. growth factor as enterohepatic to bile acid Metab. Full Text Full Text PDF PubMed Scopus Google the activity of cholesterol 7α-hydroxylase increased by in WT BDL mice, by in and serum with increased BA synthesis following were completely abolished in Cyp2c70-KO animals, were in of our the of BA synthesis in mice following BDL the presence of the expression of was abolished following BDL in both WT and KO mice that the of may not be the major for the increased BA synthesis following BDL in WT mice. The hepatic expression of Cyp8b1 was following BDL in WT mice and in KO animals The hepatic expression of was following BDL in both WT and KO animals reductions were also in both for and were for In WT not in KO animals, BDL in increased for and In the intestinal following BDL in WT and KO the of the and were and the expression of was increased in WT mice, with a in the KO animals there were a in and the and levels were in both following BDL In with in mice T. M. L. G. B. growth factor as enterohepatic to bile acid Metab. Full Text Full Text PDF PubMed Scopus Google Scholar, expression of the bile fibroblast growth factor in the liver of with 2009; PubMed Scopus Google could not expression of in the from of the not The metabolic response to BDL in WT mice is thus in to that in humans with hepatic and circulating levels of are increased and serum J. M. Rudling M. Angelin B. G. B. E. of bile acid metabolism in biliary of by and to Scopus Google Scholar, and is increased in human Bile and targets of bile acid Scholar, expression of the bile fibroblast growth factor in the liver of with 2009; PubMed Scopus Google Scholar). In with our cholesterol in KO mice was higher in WT animals, and increased in both following BDL In with the BA for were increased in BDL WT mice, such in BDL KO mice The was following BDL in KO mice not in the WT were for in The was by >50% following BDL in both WT and KO mice Compared to of was increased following BDL in WT in KO increased in both lower in the KO mice The serum markers for cholesterol and were increased by to following BDL in WT mice, a response that was in KO mice cholesterol increased following BDL in WT mice, the increase was in KO mice The cholesterol increase in WT mice was to large particles in with the formation of E. after Metab. Dis. 2019; Full Text Full Text PDF PubMed Scopus Google this response was in BDL KO the of BAs were much higher in WT in KO animals The regulation of BA metabolism is a for how molecules control their formation and by modulation of rate-limiting of synthesis and the enterohepatic circulation J.Y. Bile regulation of Lipid Res. 2009; Full Text Full Text PDF PubMed Scopus Google Scholar, in bile acid and and their of the Lipid Res. 2014; Full Text Full Text PDF PubMed Scopus Google Scholar). In to of BAs for of in the bile and in the cholesterol and from the liver and of fat and from the the of cholesterol into BAs is a major of body cholesterol knowledge on BA and cholesterol turnover has from human our of cholesterol metabolism is to a on has that there are major species differences in cholesterol, and which have the translation of data to the human such the for BA and cholesterol synthesis and the turnover and concentration of LDL in mice and rats with humans have of that MCAs in mice a key for major differences in their metabolic phenotype with humans. The of MCAs in Cyp2c70-KO mice the proposed critical of this for their formation T. Y. C. Cyp2c70 is for the species difference in bile acid metabolism between mice and Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). MCAs are the synthesis of BAs and cholesterol as well as hepatic are by in increased serum LDL-cholesterol of control of BA synthesis are MCAs are in synthesis as well as of cholesterol from the The in of hepatic cholesterol synthesis and leading to a human-like metabolic We have to that the pool of BAs is in the Cyp2c70-KO mice. in the KO mice, the synthesis of BAs is the BA is in the of KO mice. BAs were in bile from KO mice. On the other hand, to the higher for of biliary and intestinal cholesterol and other of the BAs the pool of the KO animals, which was not in the should the overall was that the levels of serum which are to be markers of cholesterol were lower in the KO We that the in BA pool size and following Cyp2c70-KO in increased activation of which should be in in levels of by this However, our in WT and KO animals a which may in the liver and in the the of BA synthesis was not by increase in hepatic of and with other such as and were in the The expression of was increased in the liver of KO In the the with and increased in the KO animals, and and the of this of the Cyp2c70 were J. J. A human-like bile acid pool by deletion of Cyp2c70 effects of activation in mice. J. Lipid Res. Scholar, T. J. T. Y. T. F. of bile acid metabolism in mouse models with bile acid Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). the of their was from they which our WT and KO animals, the differences that be to hepatic activation are not as as the that there are by which the differences in the of BAs in species differences between mice and humans regarding BA and cholesterol The of differences for of the proposed by T. J. T. Y. T. F. of bile acid metabolism in mouse models with bile acid Lipid Res. Full Text Full Text PDF PubMed Scopus Google was not in our indicated in our be to this In the KO animals, the of MCAs to be with of liver by increased liver serum liver and also in with the of T. J. T. Y. T. F. of bile acid metabolism in mouse models with bile acid Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). may be to the marked increase in BAs in the KO mice. the of the of and in the of WT animals in our study was a to that for human liver C. C. J. Bile acid in human and liver and in Full Text PDF PubMed Scopus Google Scholar). The in the KO was higher that in humans, and to that in with biliary J. M. Rudling M. Angelin B. G. B. E. of bile acid metabolism in biliary of by and to Scopus Google Scholar). despite that the pool size of BAs is in the Cyp2c70-KO mice, the of levels of such as In humans, BA synthesis is in in rats and mice, following BDL is known to in a of BA synthesis J. R.A. of cholesterol and bile acid in J. PubMed Scopus Google Scholar, J. of biliary on of in bile acid Lipid Res. Full Text PDF PubMed Google Scholar). The response has to FXR-mediated production of signaling to the liver T. M. L. G. B. growth factor as enterohepatic to bile acid Metab. Full Text Full Text PDF PubMed Scopus Google Scholar). in of the that was in animals following the of BA synthesis in WT animals was abolished in KO mice. the response to BDL in the KO mice is to that in humans, this as well as the of of hepatic despite the hepatic levels of BAs following that species differences may be in this is to have a function in liver E. after Metab. Dis. 2019; Full Text Full Text PDF PubMed Scopus Google the of BA synthesis following BDL in mice may be as part of a in this in to the increased of studies using the Cyp2c70-KO mouse should a useful to of liver in therapeutic in human disease. differences between mice and humans the of BA and cholesterol the production of cholesterol to be with that of BAs in rodents C. Angelin B. Rudling M. Bile acid synthesis in humans has a that is with cholesterol Full Text Full Text PDF PubMed Scopus Google Scholar). may be to species to The marked in cholesterol metabolism following modulation of BA pool in mice also the of of BA synthesis in humans C. Angelin B. Rudling M. in bile acid synthesis in humans is to and circulating levels of fibroblast growth factor PubMed Scopus Google in to the of disease. The human-like metabolic phenotype of the Cyp2c70-KO mice should be useful for studies exploring the and treatment of human disease, dyslipidemia, fatty liver disease, type 2 and Aguiar Vallim T.Q. Tarling E.J. Edwards P.A. Pleiotropic roles of bile acids in metabolism.Cell Metab. 2013; 17: 657-669Abstract Full Text Full Text PDF PubMed Scopus (473) Google Scholar, 3Lefebvre P. Cariou B. Lien F. Kuipers F. Staels B. Role of bile acids and bile acid receptors in metabolic regulation.Physiol. Rev. 2009; 89: 147-191Crossref PubMed Scopus (1026) Google In conclusion, have that of the major differences known to between humans and mice regarding cholesterol, and metabolism be explained to a large by the presence of hydrophilic MCAs in the differences between BAs to activation of the in the may is that other are also We that the Cyp2c70-KO mouse may be a useful in studies of the of human disease and for the of human The Arvidsson and for with bile acid bile acid bile duct ligation acid acid Animal cholesterol 7α-hydroxylase acid fibroblast growth factor muricholic acid type acid

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