Combining ASBT inhibitor and FGF15 treatments enhances therapeutic efficacy against cholangiopathy in female but not male Cyp2c70 KO mice

Hasan, Mohammad Nazmul; Chen, Jianglei; Matye, David J.; Wang, Huaiwen; Luo, Wei; Gu, Li; Clayton, Yung Dai; Du, Yi; Li, Tiangang

doi:10.1016/j.jlr.2023.100340

Cited by 5 publications

(13 citation statements)

References 59 publications

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“…The study also confirmed that the imbalanced BA-TGR5 axis could promote colonic mucosal barrier dysfunction and enhance visceral hypersensitivity (VH) in UC (Zhan et al, 2024). The expression of Cyp2c70 and FGF15 have closed relationship with impaired gut barrier (Hasan et al, 2023). In the result, the GPBAR1(TGR5) and FXR were increased treatment by PD and the expression levels of Occludin, Claudin1, Claudin5 and Zonula occludens-1 (ZO-1) protein, and the relative expression of ZO-1 and Occludin mRNA, which also related with colonic mucosal barrier, were significantly increased PD group in our previous study (Niu et al, 2023).…”

Section: Discussionsupporting

confidence: 58%

Pulsatilla decoction alleviates DSS-induced UC by activating FXR-ASBT pathways to ameliorate disordered bile acids homeostasis

Xiao,

Jia,

Liu

et al. 2024

Front. Pharmacol.

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Ethnopharmacological relevance: Pulsatilla decoction (PD) is a classical prescription for the treatment of ulcerative colitis. Previous studies have demonstrated that the therapeutic efficacy of PD is closely associated with the activation of Farnesoid X receptor (FXR). The activity of FXR is regulated by apical sodium-dependent bile acid transporter (ASBT), and the FXR-ASBT cascade reaction, centered around bile acid receptor FXR, plays a pivotal role in maintaining bile acid metabolic homeostasis to prevent the occurrence and progression of ulcerative colitis (UC).Aim of the study: To elucidate the underlying mechanism by which PD exerts its proteactive effects against Dextran Sulfate Sodium Salt (DSS)-induced ulcerative colitis, focusing on the modulation of FXR and ASBT.Materials and methods: To establish a model of acute ulcerative colitis, BALB/C mice were administered 3.5% DSS in their drinking water for consecutive 7 days. The disease activity index (DAI) was employed to evaluate the clinical symptoms exhibited by each group of mice. Goblet cell expression in colon tissue was assessed using glycogen schiff periodic acid-Schiff (PAS) and alcian blue staining techniques. Inflammatory cytokine expression in serum and colonic tissues was examined through enzyme-linked immunosorbent assay (ELISA). A PCR Array chip was utilized to screen 88 differential genes associated with the FXR-ASBT pathway in UC treatment with PD. Western blotting (WB) analysis was performed to detect protein expression levels of differentially expressed genes in mouse colon tissue.Results: The PD treatment effectively reduced the Disease Activity Index (DAI) score and mitigated colon histopathological damage, while also restoring weight and colon length. Furthermore, it significantly alleviated the severity of ulcerative colitis (UC), regulated inflammation, modulated goblet cell numbers, and restored bile acid balance. Additionally, a PCR Array analysis identified 21 differentially expressed genes involved in the FXR-ASBT pathway. Western blot results demonstrated significant restoration of FXR, GPBAR1, CYP7A1, and FGF15 protein expression levels following PD treatment; moreover, there was an observed tendency towards increased expression levels of ABCB11 and RXRα.Conclusion: The therapeutic efficacy of PD in UC mice is notable, potentially attributed to its modulation of bile acid homeostasis, enhancement of gut barrier function, and attenuation of intestinal inflammation.

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Section: Discussionsupporting

confidence: 58%

Pulsatilla decoction alleviates DSS-induced UC by activating FXR-ASBT pathways to ameliorate disordered bile acids homeostasis

Xiao,

Jia,

Liu

et al. 2024

Front. Pharmacol.

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“…Another strategy is to combine (intestinal) ASBT inhibition with repression of bile salt synthesis, in order to lower the hepatic bile salt load. This was first shown in female Cyp2c70 deficient mice, where a combination of intestinal ASBT inhibitor with FGF15 treatment reversed the cholestatic phenotype while ASBT inhibitor monotherapy was not as effective [37]. Recently, combination therapies were tested in a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-cholestasis mouse model.…”

Section: Apical Sodium-dependent Bile Salt Transporter Inhibitionmentioning

confidence: 99%

Targeting bile salt homeostasis in biliary diseases

Trampert,

Kunst,

van de Graaf

2024

Current Opinion in Gastroenterology

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Purpose of review Advances in the understanding of bile salt synthesis, transport and signalling show the potential of modulating bile salt homeostasis as a therapeutic strategy in cholestatic liver diseases. Here, recent developments in (pre)clinical research in this field is summarized and discussed. Recent findings Inhibition of the apical sodium-dependent bile salt transporter (ASBT) and Na+-taurocholate cotransporting polypeptide (NTCP) seems effective against cholestatic liver diseases, as well as Farnesoid X receptor (FXR) agonism or a combination of both. While approved for the treatment of primary biliary cholangitis (PBC) and intrahepatic cholestasis of pregnancy (ICP), ursodeoxycholic acid (UDCA) has retrospectively shown carefully promising results in primary sclerosing cholangitis (PSC). The side chain shortened derivate norUDCA is of further therapeutic interest since its mechanisms of action are independent of the bile salt transport machinery. In the pathogenesis of sclerosing cholangiopathies, a skewed T-cell response with alterations in gut microbiota and bile salt pool compositions are observed. In PSC pathogenesis, the bile salt receptor Takeda G-protein-coupled receptor 5 (TGR5) in cholangiocytes is implicated, whilst in immunoglobulin G4-related cholangitis the autoantigens annexin A11 and laminin 511-E8 are involved in protecting cholangiocytes. Summary Modulating bile salt homeostasis has proven a promising treatment strategy in models of cholestasis and are continuously being further developed. Confirmatory clinical studies are needed in order to assess the proposed treatment strategies in patients allowing for a broader therapeutic arsenal in the future.

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“…This gut bile acid composition in Cyp2c70 KO mice is different from human gut that is exposed to a bile acid mixture consisting of primarily deconjugated CDCA, CA and DCA with only trace amount of LCA [12,13]. So far, the Cyp2c70 KO mice have been used as a new model to investigate the treatment effects against bile acid-induced cholangiopathy and gut barrier dysfunction by FXR agonist, fibroblast growth factor 15 (FGF15), ASBT inhibitor, and UDCA [8 ▪ ,10 ▪ ,14,15,16 ▪ ]. Reduction in either bile acid exposure or bile acid pool hydrophobicity index alleviates liver injury in the Cyp2c70 KO mice.…”

Section: Cyp2c70 Mediates Muricholic Acid Synthesis In Micementioning

confidence: 99%

Bile acids as metabolic regulators: an update

Chiang

2023

Current Opinion in Gastroenterology

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Purpose of reviewThis review aims to provide a concise update on recent advances in understanding of the bile acid metabolism and signaling in health and diseases.Recent findingsCYP2C70 has been identified as the murine cytochrome p450 enzyme that mediates the synthesis of muricholic acids to account for the major different bile acid composition between human and mice. Several studies have linked nutrient sensing bile acid signaling to the regulation of hepatic autophagy-lysosome activity, an integral pathway of the cellular adaptive response to starvation. Distinct bile acid-mediated signaling mechanisms have been shown to contribute to the complex metabolic changes post bariatric surgery, suggesting that pharmacological manipulation of the enterohepatic bile acid signaling could be a potential nonsurgical alternative to weight loss surgery.SummaryBasic and clinical studies have continued to discover novel roles of the enterohepatic bile acid signaling in regulation of key metabolic pathways. Such knowledge forms the molecular basis needed for developing safe and effective bile acid-based therapeutics for treating metabolic and inflammatory diseases.

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Combining ASBT inhibitor and FGF15 treatments enhances therapeutic efficacy against cholangiopathy in female but not male Cyp2c70 KO mice

Cited by 5 publications

References 59 publications

Pulsatilla decoction alleviates DSS-induced UC by activating FXR-ASBT pathways to ameliorate disordered bile acids homeostasis

Pulsatilla decoction alleviates DSS-induced UC by activating FXR-ASBT pathways to ameliorate disordered bile acids homeostasis

Targeting bile salt homeostasis in biliary diseases

Bile acids as metabolic regulators: an update

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