Combined deletion of Fxr and Shp in mice induces Cyp17a1 and results in juvenile onset cholestasis

Anakk, Sayeepriyadarshini; Watanabe, Mitsuhiro; Ochsner, Scott A.; McKenna, Neil J.; Finegold, Milton J.; Moore, David D.

doi:10.1172/jci42846

Cited by 108 publications

(144 citation statements)

References 75 publications

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“…Also, the importance of HDAC7 in the feedback regulation of CYP7A1 has been reported, revealing HDAC7 as a potential target for treating hypercholesterolemia (37). Although BAs have beneficial roles in removing excess cholesterol and counteracting obesity by reducing TG levels, abnormally elevated hepatic BA levels are associated with hepatobiliary disease, like cholestasis, as recently demonstrated in SHP-KO (38) and SHP/FXR-KO mouse studies (39). In this work, we have shown the crucial role of phosphorylation of SHP at a single site by PKC in BA signal-induced epigenomic regulation of liver metabolic genes.…”

Section: Discussionmentioning

confidence: 90%

Bile Acid Signal-induced Phosphorylation of Small Heterodimer Partner by Protein Kinase Cζ Is Critical for Epigenomic Regulation of Liver Metabolic Genes

Seok

Kanamaluru

Xiao

et al. 2013

Journal of Biological Chemistry

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Background: Small heterodimer partner (SHP) is a key mediator of bile acid signaling. Results: Bile acid signal-induced phosphorylation at Thr-55 by protein kinase C is important for SHP-mediated recruitment of chromatin modifiers and histone modifications. Conclusion: Thr-55 phosphorylation is critical for epigenomic regulation of liver metabolic genes. Significance: SHP Thr-55 phosphorylation may potentially provide a therapeutic target for bile acid-related diseases.

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Section: Discussionmentioning

confidence: 90%

Bile Acid Signal-induced Phosphorylation of Small Heterodimer Partner by Protein Kinase Cζ Is Critical for Epigenomic Regulation of Liver Metabolic Genes

Seok

Kanamaluru

Xiao

et al. 2013

Journal of Biological Chemistry

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“…Whole-body FXR-deficient mice exhibited a significant accumulation of hepatic and plasma triglyceride levels as well as of VLDL, LDL, and HDL (46,47). Other studies revealed that the hepatic FXR/SHP pathway inhibits SREBP1C and microsomal triglyceride transfer proteinmediated (MTP-mediated) hepatic lipogenesis (48)(49)(50). However, activation of FXR with the synthetic agonist GW4064 increased HFD-induced lipid accumulation in the liver, partially due to a significant reduction in BA pool size and energy expenditure (51).…”

Section: Discussionmentioning

confidence: 99%

Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease

Jiang¹,

Xie²,

Li³

et al. 2014

J. Clin. Invest.

560

513

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. measured for 8 days. The feces were collected every 2 days for 8 days. Ileal and fecal lipids were extracted as described in the Supplemental Methods. Triglycerides were measured with a triglyceride colorimetric assay kit (Bioassay Systems). Free fatty acids (FFAs) were measured using reagents from Wako.Statistics. Experimental values are presented as the mean ± SD. Statistical analyses were performed using the 2-tailed Student's t test and 1-way ANOVA with Tukey's confirmation. Weighted UniFrac analysis to assess changes in bacterial abundance was performed on the Galaxy web-based platform. Statistical models including PCA, PLS-DA, and OPLS-DA were established to represent the major latent variables in the data matrix. P values of less than 0.05 were considered significant. Study approval. All animal studies were performed in accordance with the Institute of Laboratory Animal Resources guidelines and approved by the IACUC of the NCI.

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“…In the subsequent study, examining the expression of FXR signaling-related proteins in hepatocytes, the mechanisms underlying the effects of bile acid and FXR on lipid metabolism and liver regeneration were investigated. Activated FXR stimulated expression of SHP, which integrated with the liver receptor homolog and inhibited transcription of CYP7A1 (31,32). Bile acid is known to be a regulator of cysteine sulfinic acid decarboxylase via mechanisms shared in part with CYP7A1, and may affect cholesterol via CYP7A1 through the downregulation of the hepatic FXR/SHP pathway (33,34).…”

Section: Discussionmentioning

confidence: 99%

Bile acid promotes liver regeneration via farnesoid X receptor signaling pathways in rats

Ding

Yang

et al. 2015

Molecular Medicine Reports

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Abstract. Bile acids, which are synthesized from cholesterol in the hepatocytes of the liver, are amphipathic molecules with a steroid backbone. Studies have shown that bile acid exhibits important effects on liver regeneration. However, the mechanism underlying these effects remains unclear. The aim of the present study was to investigate the effect of bile acid and the farnesoid X receptor (FXR) on hepatic regeneration and lipid metabolism. Rats were fed with 0.2% bile acid or glucose for 7 days and then subjected to a 50 or 70% hepatectomy. Hepatic regeneration rate, serum and liver levels of bile acid, and expression of FXR and Caveolin-1, were detected at 24, 48 or 72 h following hepatectomy. The expression of proliferating cell nuclear antigen (PCNA) in the liver was measured using immunohistochemistry at the end of the study. Hepatocytes isolated from rats were treated with bile acid, glucose, FXR agonist and FXR antagonist, separately or in combination. Lipid metabolism, the expression of members of the FXR signaling pathway and energy metabolism-related factors were measured using ELISA kits or western blotting. Bile acid significantly increased the hepatic regeneration rate and the expression of FXR, Caveolin-1 and PCNA. Levels of total cholesterol and high density lipoprotein were increased in bile acid-or FXR agonist-treated hepatocytes in vitro. Levels of triglyceride, low density lipoprotein and free fatty acid were decreased. In addition, bile acid and FXR agonists increased the expression of bile salt export pump and small heterodimer partner, and downregulated the expression of apical sodium-dependent bile acid transporter, Na + /taurocholate cotransporting polypeptide and cholesterol 7α-hydroxylase. These results suggested that physiological concentrations of bile acid may promote liver regeneration via FXR signaling pathways, and may be associated with energy metabolism. IntroductionLiver regeneration is important in the recovery from injury induced by surgery, trauma, poisoning, infection, necrosis or liver transplantation (1). Consequently, research investigating the improvement of the regeneration ability of the liver, is of great significance. During regeneration, quiescent mature hepatocytes reenter the cell cycle in order to proliferate and divide, thus leading to hepatic regeneration without the involvement of stem cells. Although the exact mechanisms have not been fully characterized, a study demonstrated that liver regeneration primarily comprises cell proliferation, lipid metabolism, various growth factors, and a number of cytokines and their signaling pathways (2).Bile acid, which is synthesized from cholesterol, is the chief components of bile. The primary functions of bile are to digest the fat soluble molecules in food and to aid in the intestinal absorption of lipids in vivo. Recent studies have shown that bile acid acts as a signaling molecule by activating signaling pathways, and that it participates in the process of liver regeneration (3,4). A number of transport proteins fo...

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Combined deletion of Fxr and Shp in mice induces Cyp17a1 and results in juvenile onset cholestasis

Cited by 108 publications

References 75 publications

Bile Acid Signal-induced Phosphorylation of Small Heterodimer Partner by Protein Kinase Cζ Is Critical for Epigenomic Regulation of Liver Metabolic Genes

Bile Acid Signal-induced Phosphorylation of Small Heterodimer Partner by Protein Kinase Cζ Is Critical for Epigenomic Regulation of Liver Metabolic Genes

Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease

Bile acid promotes liver regeneration via farnesoid X receptor signaling pathways in rats

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