Mechanism of action of the bile acid receptor TGR5 in obesity

Lun, Weijun; Yan, Qihao; Guo, Xinghua; Zhou, Minchuan; Bai, Yan; He, Jincan; Cao, Hua; Che, Qishi; Guo, Jiao; Su, Zhengquan

doi:10.1016/j.apsb.2023.11.011

Cited by 12 publications

(2 citation statements)

References 198 publications

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“…Osta-Ostb also appears to play a major role in protecting gut barrier injury Frontiers in Pharmacology frontiersin.org (Ferrebee et al, 2018). The expression imbalance of ASBT and OSTa-OSTb is closely related to intestinal cell injury (Lun et al, 2024). 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).…”

Section: Discussionmentioning

confidence: 53%

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: Discussionmentioning

confidence: 53%

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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“…However, FXR also prevents the expression of sterol regulatory element-binding protein 1c and stimulates peroxisome proliferator-activated receptor alpha that inhibits lipid accumulation in the liver and increases the efficiency of β-oxidation[ 56 , 57 ]. Activation of TGR5 increases glucagon-like peptide-1 (GLP-1) secretion, leading to increased glucose-dependent insulin secretion and reduced appetite, by inhibition of neuropeptide Y (NPY) and agouti-related neuropeptide neurons in the arcuate area[ 58 , 59 ]. Furthermore, BA-induced activation of the TGR5 receptor on Kupffer cells has been shown to inhibit LPS-induced cytokine expression, suggesting its potential role in the immune response[ 60 ].…”

Section: Gut-liver Axis and Related Pathophysiologymentioning

confidence: 99%

Role of gut-liver axis and glucagon-like peptide-1 receptor agonists in the treatment of metabolic dysfunction-associated fatty liver disease

Rochoń,

Kalinowski,

Szymanek-Majchrzak

et al. 2024

World J Gastroenterol

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Metabolic dysfunction-associated fatty liver disease (MAFLD) is a hepatic manifestation of the metabolic syndrome. It is one of the most common liver diseases worldwide and shows increasing prevalence rates in most countries. MAFLD is a progressive disease with the most severe cases presenting as advanced fibrosis or cirrhosis with an increased risk of hepatocellular carcinoma. Gut microbiota play a significant role in the pathogenesis and progression of MAFLD by disrupting the gut-liver axis. The mechanisms involved in maintaining gut-liver axis homeostasis are complex. One critical aspect involves preserving an appropriate intestinal barrier permeability and levels of intestinal lumen metabolites to ensure gut-liver axis functionality. An increase in intestinal barrier permeability induces metabolic endotoxemia that leads to steatohepatitis. Moreover, alterations in the absorption of various metabolites can affect liver metabolism and induce liver steatosis and fibrosis. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a class of drugs developed for the treatment of type 2 diabetes mellitus. They are also commonly used to combat obesity and have been proven to be effective in reversing hepatic steatosis. The mechanisms reported to be involved in this effect include an improved regulation of glycemia, reduced lipid synthesis, β-oxidation of free fatty acids, and induction of autophagy in hepatic cells. Recently, multiple peptide receptor agonists have been introduced and are expected to increase the effectiveness of the treatment. A modulation of gut microbiota has also been observed with the use of these drugs that may contribute to the amelioration of MAFLD. This review presents the current understanding of the role of the gut-liver axis in the development of MAFLD and use of members of the GLP-1 RA family as pleiotropic agents in the treatment of MAFLD.

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The obeticholic acid can positively regulate the cancerous behavior of MCF7 breast cancer cell line

Rahmani,

Eivazi,

Emamgholipour

et al. 2024

Mol Biol Rep

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Mechanism of action of the bile acid receptor TGR5 in obesity

Cited by 12 publications

References 198 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

Role of gut-liver axis and glucagon-like peptide-1 receptor agonists in the treatment of metabolic dysfunction-associated fatty liver disease

The obeticholic acid can positively regulate the cancerous behavior of MCF7 breast cancer cell line

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