Intestinal nuclear bile acid receptor FXR and cholestasis

López-Velázquez, Jorge A.; Castro-Torres, Ibrahim Guillermo; Sánchez-Valle, Vicente; Méndez-Sánchez, Nahúm

doi:10.1016/s1665-2681(19)31504-2

Cited by 5 publications

(4 citation statements)

References 14 publications

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“…In cholestasis, the accumulation of BAs induces a compensatory response aiming to repress the expression of CYP7A1, the rate-limiting step of BA synthesis from cholesterol, and CYP8B1, which is mediated by FXR-FGF15/19 activation. 28,29 As expected, we observed a decrease of CYP8B1 in PFIC3 livers (Figure 6A) that was confirmed in the liver of MDR2 À/À mice, where also downregulation of CYP7A1 was demonstrated (Figure 6B). We also observed a marked decrease of PEPCK, G6PASE, and IDH3A in MDR2 À/À livers of 5and 8-month-old mice, further supporting the activation of the FGF15/19 signaling and suggesting a glycolysis activation.…”

Section: Metabolic Rewiring In Pfic3 Liverssupporting

confidence: 85%

Molecular basis of progressive familial intrahepatic cholestasis 3. A proteomics study

Guerrero,

Carmona‐Rodríguez,

Santos

et al. 2024

BioFactors

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Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a severe rare liver disease that affects between 1/50,000 and 1/100,000 children. In physiological conditions, bile is produced by the liver and stored in the gallbladder, and then it flows to the small intestine to play its role in fat digestion. To prevent tissue damage, bile acids (BAs) are kept in phospholipid micelles. Mutations in phosphatidyl choline transporter ABCB4 (MDR3) lead to intrahepatic accumulation of free BAs that result in liver damage. PFIC3 onset usually occurs at early ages, progresses rapidly, and the prognosis is poor. Currently, besides the palliative use of ursodeoxycholate, the only available treatment for this disease is liver transplantation, which is really challenging for short‐aged patients. To gain insight into the pathogenesis of PFIC3 we have performed an integrated proteomics and phosphoproteomics study in human liver samples to then validate the emerging functional hypotheses in a PFIC3 murine model. We identified 6246 protein groups, 324 proteins among them showing differential expression between control and PFIC3. The phosphoproteomic analysis allowed the identification of 5090 phosphopeptides, from which 215 corresponding to 157 protein groups, were differentially phosphorylated in PFIC3, including MDR3. Regulation of essential cellular processes and structures, such as inflammation, metabolic reprogramming, cytoskeleton and extracellular matrix remodeling, and cell proliferation, were identified as the main drivers of the disease. Our results provide a strong molecular background that significantly contributes to a better understanding of PFIC3 and provides new concepts that might prove useful in the clinical management of patients.

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Section: Metabolic Rewiring In Pfic3 Liverssupporting

confidence: 85%

Molecular basis of progressive familial intrahepatic cholestasis 3. A proteomics study

Guerrero,

Carmona‐Rodríguez,

Santos

et al. 2024

BioFactors

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“…4D–F). FXR is an important BA receptor and essential to the BA homeostasis141516. We here showed that the hepatic FXR expression was lower in IF patients compared to controls (Fig.…”

Section: Resultsmentioning

confidence: 51%

Altered systemic bile acid homeostasis contributes to liver disease in pediatric patients with intestinal failure

Xiao

Cao

Zhou

et al. 2016

Sci Rep

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Intestinal failure (IF)-associated liver disease (IFALD), as a major complication, contributes to significant morbidity in pediatric IF patients. However, the pathogenesis of IFALD is still uncertain. We here investigate the roles of bile acid (BA) dysmetabolism in the unclear pathogenesis of IFALD. It found that the histological evidence of pediatric IF patients exhibited liver injury, which was characterized by liver bile duct proliferation, inflammatory infiltration, hepatocyte apoptosis and different stages of fibrosis. The BA compositions were altered in serum and liver of pediatric IF patients, as reflected by a primary BA dominant composition. In IF patients, the serum FGF19 levels decreased significantly, and were conversely correlated with ileal inflammation grades (r = −0.50, p < 0.05). In ileum, the inflammation grades were inversely associated with farnesoid X receptor (FXR) expression (r = −0.55, p < 0.05). In liver, the expression of induction of the rate-limiting enzyme in bile salt synthesis, cytochrome P450 7a1 (CYP7A1) increased evidently. In conclusion, ileum inflammation decreases FXR expression corresponding to reduce serum FGF19 concentration, along with increased hepatic bile acid synthesis, leading to liver damages in IF patients.

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“…In cholestasis, the accumulation of BAs induces a compensatory response aiming to repress the expression of CYP7A1, the rate limiting step of BA synthesis from cholesterol, and CYP8B1, which is mediated by FXR-FGF15/19 activation 27,28 . As expected, we observed a decrease of CYP8B1 in PFIC3 livers (Figure 6A) that was confirmed in the liver of MDR2-/-mice, where also down-regulation of CYP7A1 was demonstrated (Figure 6B).…”

Section: Metabolic Rewiring In Pfic3 Liversmentioning

confidence: 99%

Molecular basis of Progressive Familial Intrahepatic Cholestasis 3. A proteomics study

Guerrero

Carmona-Rodríguez

Santos

et al. 2023

Preprint

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Background and aims: Progressive familiar intrahepatic cholestasis type 3 (PFIC3) is a severe rare liver disease which affects between 1/50,000 to 1/100,000 children. In physiological conditions, bile is produced by the liver and stored in the gallbladder, then it flows to the small intestine to play its role in fat digestion. To prevent tissue damage, bile acids are kept into phospholipid micelles. Mutations in phosphatidyl choline transporter ABCB4 (MDR3) lead to intrahepatic accumulation of free bile acids that results in liver damage. PFIC3 onset occurs usually at early ages, progress rapidly and the prognosis is poor. Currently, besides the palliative use of ursodeoxycholate, the only available treatment for this disease is liver transplantation, which is really challenging for short-aged patients. Methods: To gain insight into the pathogenesis of PFIC3 we have performed an integrated proteomics and phosphoproteomics study in human liver samples to then validate the emerging functional hypotheses in a PFIC3 murine model. Results: We identified 6,246 protein groups, 324 proteins among them showing differential expression between control and PFIC3. The phosphoproteomic analysis allowed the identification of 5,090 phosphopeptides, from which 215 corresponding to 157 protein groups, were differentially phosphorylated in PFIC3, including MDR3. Regulation of essential cellular processes and structures, such as inflammation, metabolic reprograming, cytoskeleton and extracellular matrix remodeling and cell proliferation were identified as main drivers of the disease. Conclusion: Our results provide a strong molecular background that significantly contributes to a better understanding of PFIC3 and provides new concepts that might prove useful in the clinical management of patients.

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Intestinal nuclear bile acid receptor FXR and cholestasis

Cited by 5 publications

References 14 publications

Molecular basis of progressive familial intrahepatic cholestasis 3. A proteomics study

Molecular basis of progressive familial intrahepatic cholestasis 3. A proteomics study

Altered systemic bile acid homeostasis contributes to liver disease in pediatric patients with intestinal failure

Molecular basis of Progressive Familial Intrahepatic Cholestasis 3. A proteomics study

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