Bile acids and their signaling pathways are increasingly recognized as potential therapeutic targets for cholestatic and metabolic liver diseases. This review summarizes new insights in bile acid ...physiology, focusing on regulatory roles of bile acids in the control of immune regulation and on effects of pharmacological modulators of bile acid signaling pathways in human liver disease. Recent mouse studies have highlighted the importance of the interactions between bile acids and gut microbiome. Interfering with microbiome composition may be beneficial for cholestatic and metabolic liver diseases by modulating formation of secondary bile acids, as different bile acid species have different signaling functions. Bile acid receptors such as FXR, VDR, and TGR5 are expressed in a variety of cells involved in innate as well as adaptive immunity, and specific microbial bile acid metabolites positively modulate immune responses of the host. Identification of Cyp2c70 as the enzyme responsible for the generation of hydrophilic mouse/rat-specific muricholic acids has allowed the generation of murine models with a human-like bile acid composition. These novel mouse models will aid to accelerate translational research on the (patho)physiological roles of bile acids in human liver diseases .
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Bile acids (BAs) facilitate intestinal absorption of lipid-soluble nutrients and modulate various metabolic pathways through the farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5. ...These receptors are targets for therapy in cholestatic and metabolic diseases. However, dissimilarities in BA metabolism between humans and mice complicate translation of preclinical data. Cytochrome P450 family 2 subfamily c polypeptide 70 (CYP2C70) was recently proposed to catalyze the formation of rodent-specific muricholic acids (MCAs). With CRISPR/Cas9-mediated somatic genome editing, we generated an acute hepatic Cyp2c70 knockout mouse model (Cyp2c70ako) to clarify the role of CYP2C70 in BA metabolism in vivo and evaluate whether its activity modulates effects of pharmacologic FXR activation on cholesterol homeostasis. In Cyp2c70ako mice, chenodeoxycholic acid (CDCA) increased at the expense of βMCA, resulting in a more hydrophobic human-like BA pool. Tracer studies demonstrated that, in vivo, CYP2C70 catalyzes the formation of βMCA primarily by sequential 6β-hydroxylation and C7-epimerization of CDCA, generating αMCA as an intermediate metabolite. Physiologically, the humanized BA composition in Cyp2c70ako mice blunted the stimulation of fecal cholesterol disposal in response to FXR activation compared with WT mice, predominantly due to reduced stimulation of transintestinal cholesterol excretion. Thus, deletion of hepatic Cyp2c70 in adult mice translates into a human-like BA pool composition and impacts the response to pharmacologic FXR activation. This Cyp2c70ako mouse model may be a useful tool for future studies of BA signaling and metabolism that informs human disease development and treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Bile acids (BAs) and their signaling pathways have been identified as therapeutic targets for liver and metabolic diseases. We generated Cyp2c70−/− (KO) mice that were not able to convert ...chenodeoxycholic acid into rodent-specific muricholic acids (MCAs) and, hence, possessed a more hydrophobic, human-like BA pool. Recently, we have shown that KO mice display cholangiopathic features with the development of liver fibrosis. The aim of this study was to determine whether BA sequestration modulates liver pathology in Western type-diet (WTD)-fed KO mice. The BA sequestrant colesevelam was mixed into the WTD (2% w/w) of male Cyp2c70+/+ (WT) and KO mice and the effects were evaluated after 3 weeks of treatment. Colesevelam increased fecal BA excretion in WT and KO mice and reduced the hydrophobicity of biliary BAs in KO mice. Colesevelam ameliorated diet-induced hepatic steatosis in WT mice, whereas KO mice were resistant to diet-induced steatosis and BA sequestration had no additional effects on liver fat content. Total cholesterol concentrations in livers of colesevelam-treated WT and KO mice were significantly lower than those of untreated controls. Of particular note, colesevelam treatment normalized plasma levels of liver damage markers in KO mice and markedly decreased hepatic mRNA levels of fibrogenesis-related genes in KO mice. Lastly, colesevelam did not affect glucose excursions and insulin sensitivity in WT or KO mice. Our data show that BA sequestration ameliorates liver pathology in Cyp2c70−/− mice with a human-like bile acid composition without affecting insulin sensitivity.
There is a growing awareness that individual bile acid species exert different physiological functions, beyond their classical roles in bile formation and fat absorption, due to differential ...stimulatory effects on the bile-acid-activated receptors farnesoid X receptor (FXR) and takeda G receptor 5 (TGR5). This review integrates recent findings on the role of individual bile acids and their receptors in metabolic control, with special emphasis on cholesterol homeostasis.
The consequences of altered bile acid metabolism, for example, in type 2 diabetes and during aging, on metabolic control is increasingly recognized but full impact hereof remains to be elucidated. These effects interact with those of newly developed pharmacological FXR and TGR5 modulators that aim to improve metabolic health. Studies in genetically modified mice have provided important new insights, for example, establishment of the role of intestinal FXR in control of the transintestinal cholesterol excretion pathway. However, translation from mice to men is hampered by the presence of rodent-specific bile acid species with special features.
Specific bile acids and their signaling pathways play important roles in control of (cholesterol) metabolism. Deeper insight into the interactions between endogenous (i.e., bile acids) and pharmacological modulators of FXR and TGR5 is needed to optimize therapeutic benefit of the latter. The recent identification of cytochrome P450 2C70 as key enzyme in the formation of rodent-specific hydrophilic muricholic acids allows for the development of adequate mouse models for this purpose.
Bile acids (BAs) and their signaling pathways have been identified as therapeutic targets for liver and metabolic diseases. We generated Cyp2c70sup.−/− (KO) mice that were not able to convert ...chenodeoxycholic acid into rodent-specific muricholic acids (MCAs) and, hence, possessed a more hydrophobic, human-like BA pool. Recently, we have shown that KO mice display cholangiopathic features with the development of liver fibrosis. The aim of this study was to determine whether BA sequestration modulates liver pathology in Western type-diet (WTD)-fed KO mice. The BA sequestrant colesevelam was mixed into the WTD (2% w/w) of male Cyp2c70sup.+/+ (WT) and KO mice and the effects were evaluated after 3 weeks of treatment. Colesevelam increased fecal BA excretion in WT and KO mice and reduced the hydrophobicity of biliary BAs in KO mice. Colesevelam ameliorated diet-induced hepatic steatosis in WT mice, whereas KO mice were resistant to diet-induced steatosis and BA sequestration had no additional effects on liver fat content. Total cholesterol concentrations in livers of colesevelam-treated WT and KO mice were significantly lower than those of untreated controls. Of particular note, colesevelam treatment normalized plasma levels of liver damage markers in KO mice and markedly decreased hepatic mRNA levels of fibrogenesis-related genes in KO mice. Lastly, colesevelam did not affect glucose excursions and insulin sensitivity in WT or KO mice. Our data show that BA sequestration ameliorates liver pathology in Cyp2c70sup.−/− mice with a human-like bile acid composition without affecting insulin sensitivity.
Background Nutritional conditions during fetal life influence the risk of the development of metabolic syndrome and cardiovascular diseases in adult life (metabolic programming). Impaired glucose ...tolerance and dysregulated fatty acid metabolism are hallmarks of metabolic syndrome. Objective We aimed to establish a mouse model of metabolic programming focusing on the sex-specific effects of a maternal low-protein diet during gestation on glucose and lipid metabolism in the adult offspring. Methods Pregnant C57BL/6 mice received a control or a low-protein diet (18% vs 9% casein) throughout gestation. Male and female offspring received a low-fat or a high-fat diet from 6 to 22 weeks of age. Results Maternal low-protein diet during gestation led to deteriorated insulin sensitivity on high-fat feeding in female offspring, as determined by biochemical and microarray analyses. Female offspring of control diet–fed dams were relatively resistant to high-fat diet–induced metabolic dysregulation. In contrast, maternal low-protein diet did not specifically affect the metabolic parameters addressed in male offspring. In males, the high-fat diet led to insulin insensitivity regardless of the diet of the dam. Conclusions Our findings show that fetal malnutrition has a limited impact on male mouse offspring, yet it does influence the metabolic response to a high-fat diet in females. These findings may have implications for future early diagnostics in metabolic syndrome and for the development of sex-specific treatment regimens.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Intrauterine malnutrition is associated with increased susceptibility to chronic diseases in adulthood. Growth-restricted infants display a less favorable lipid profile already shortly postnatal. ...Maternal low protein diet (LPD) during gestation is a well-defined model of fetal programming in rodents and affects lipid metabolism of the offspring. Effects of LPD throughout gestation on physiologic relevant parameters of lipid metabolism are unclear. We aimed to determine effects of LPD on maternal-fetal cholesterol fluxes and fetal lipid synthesis in mice. Pregnant mice (dams) were fed with a control (18% casein) or an LPD (9% casein) from E0.5 onward. We quantified maternal-fetal cholesterol transport and maternal cholesterol absorption at E19.5 using stable isotopes. We determined fetal lipid biosynthesis at E19.5, after administration of (1-C)-acetate from E17.5 onward. LPD did not change fetal and maternal plasma and hepatic concentrations of cholesterol and triglycerides. LPD affected neither the magnitudes of maternal-fetal cholesterol flux, maternal cholesterol absorption, nor fetal synthesis of cholesterol and palmitate (both groups, approximately 14% and approximately 13%, respectively). We conclude that LPD throughout gestation in mice does not affect maternal-fetal cholesterol transport, fetal cholesterol or fatty acid synthesis, indicating that programming effects of LPD are not mediated by short-term changes in maternal-fetal lipid metabolism.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
1 Departments of Pediatrics and
2 Laboratory Medicine, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
...Submitted 9 January 2009
; accepted in final form 26 August 2009
There is increasing evidence that the metabolic state of the mother during pregnancy affects long-term glucose and lipid metabolism of the offspring. The liver X receptors (LXR) and -β are key regulators of cholesterol, fatty acid, and glucose metabolism. LXRs are activated by oxysterols and expressed in fetal mouse liver from day 10 of gestation onward. In the present study, we aimed to elucidate whether in utero pharmacological activation of LXR would influence fetal fatty acid and glucose metabolism and whether this would affect lipid homeostasis at adult age. Exposure of pregnant mice to the synthetic LXR agonist T0901317 increased hepatic mRNA expression levels of Lxr target genes and hepatic and plasma triglyceride levels in fetuses and dams. T0901317 treatment increased absolute de novo synthesis and chain elongation of hepatic oleic acid in dams and fetuses. T0901317 exposure in utero influenced lipid metabolism in adulthood in a sex-specific manner; hepatic triglyceride content was increased (+45%) in male offspring and decreased in female offspring (–42%) when they were fed a regular chow diet compared with untreated sex controls. Plasma and hepatic lipid contents and hepatic gene expression patterns in adult male or female mice fed a high-fat diet were not affected by T0901317 pretreatment. We conclude that LXR treatment of pregnant mice induces immediate effects on lipid metabolism in dams and fetuses. Despite the profound changes during fetal life, long-term effects appeared to be rather mild and sex selective without modulating the lipid response to a high-fat diet.
fetus; lipid metabolism; gestation; long-term effects
Address for reprint requests and other correspondence: T. Plösch, Dept. of Pediatrics, Univ. Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands (e-mail: t.plosch{at}med.umcg.nl ).
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