The Immunomodulatory Role of Bile Acids

Sipka, Sándor; Bruckner, Géza

doi:10.1159/000366100

Cited by 68 publications

(64 citation statements)

References 65 publications

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“…Bile acids are considered to be both detergent molecules that facilitate the solubilization of cheolesterol and absorption of lipids and regulatory molecules that activate five distinct receptors (farnesoid X receptor, pregnane X receptor, constitutive androstane receptor, vitamin D receptor and G protein-coupled receptor) and cell signaling pathways (c-jun N-terminal kinase 1/2, AKT and ERK1/2) in cells in the liver and gastrointestinal tract (38,39). Hepatocytes synthesize bile acids that secrete into the bile and are stored in the gallbladder (40).…”

Section: Discussionmentioning

confidence: 99%

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Phosphorylation of Bcl-2 plays an important role in glycochenodeoxycholate-induced survival and chemoresistance in HCC

et al. 2017

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Abstract. Hepatocellular carcinoma (HCC) is a highly malignant tumor and can evolve rapidly to resistance to chemotherapies. Glycochenodeoxycholate (GCDA), which is toxic and hydrophobic, is the main ingredient in the bile and associated with carcinogenesis of gastrointenstinal tumors. Bcl-2 is the most important anti-apoptotic protein and overexpressed in various human tumors. In the present study, we found that GCDA can induce the chemoresistance of human liver cancer cells and specific depletion of Bcl-2 by RNA interference blocks GCDA-stimulated chemoresistance, which indicate the pivotal role of Bcl-2 in such process. Mechanistically, GCDA simultaneously stimulates phosphorylation of Bcl-2 at Ser70 site and activates extracellular signal-regulated kinase 1/2 (ERK1/2), and inhibition of ERK1/2 by PD98059 (MAPK/ERK1/2 inhibitor) or siRNA (targeting ERK1/2) suppresses GCDA-stimulated phosphorylation of Bcl-2 and significantly attenuates the survival and chemoresistance induced by GCDA in liver cancer cells. Thus, GCDA-induced survival and chemoresistance of liver cancer cells may occur through activation of Bcl-2 by phosphorylation at Ser70 site through MAPK/ERK1/2 pathway, which may contribute to the development of human liver cancer and chemoresistance.

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Section: Discussionmentioning

confidence: 99%

“…This process is known as enterohepatic circulation of bile acids (40). Recycling of bile acids/salts between the liver and intestine occurs 6-10 times each day and transports 20-40 g bile acids (39). Bile salts and bile acids are considered to be potential carcinogens.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of Bcl-2 plays an important role in glycochenodeoxycholate-induced survival and chemoresistance in HCC

et al. 2017

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“…CAR, originally reported as a nuclear receptor regulating the response to xenobiotics, is another nuclear receptor activated by BA (Zhang et al 2004, Huang et al 2006, Sipka & Bruckner 2014. It is interesting to note that CAR has been marked as an anti-obesity nuclear receptor improving insulin sensitivity (Gao et al 2009) as well as lipid metabolism (Maglich et al 2009) and thyroid functions (Maglich et al 2004).…”

Section: Cellular Targets Of Bamentioning

confidence: 99%

“…BA have also been shown to have potent immunosuppressive effects (Sipka & Bruckner 2014). Obesity is associated with a chronic, low-grade inflammation (termed metabolic inflammation), which is an important contributor to the initiation and progression of NAFLD, insulin resistance, T2DM and atherosclerosis (Gregor & Hotamisligil 2011).…”

Section: Cellular Targets Of Bamentioning

confidence: 99%

“…Bile acids (BA), which for decades were considered to only be involved in lipid digestion in the intestinal lumen and cholesterol solubilization in the bile, now seem to have pleiotropic effects: contributing to the homeostasis of lipids, glucose and other metabolic substrates (Li & Chiang 2014, affecting immune system functions (Sipka & Bruckner 2014) as well as gut microbiome composition (Ridlon et al 2014). By binding to multiple cytoplasmic as well as nuclear receptors in various organs and tissues, they act as real hormones.…”

Section: Introductionmentioning

confidence: 99%

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The role of bile acids in metabolic regulation

Vı́tek¹,

Haluzı́k²

2016

Journal of Endocrinology

109

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Bile acids (BA), long believed to only have lipid-digestive functions, have emerged as novel metabolic modulators. They have important endocrine effects through multiple cytoplasmic as well as nuclear receptors in various organs and tissues. BA affect multiple functions to control energy homeostasis, as well as glucose and lipid metabolism, predominantly by activating the nuclear farnesoid X receptor and the cytoplasmic G protein-coupled BA receptor TGR5 in a variety of tissues. However, BA also are aimed at many other cellular targets in a wide array of organs and cell compartments. Their role in the pathogenesis of diabetes, obesity and other 'diseases of civilization' becomes even more clear. They also interact with the gut microbiome, with important clinical implications, further extending the complexity of their biological functions. Therefore, it is not surprising that BA metabolism is substantially modulated by bariatric surgery, a phenomenon contributing favorably to the therapeutic effects of these surgical procedures. Based on these data, several therapeutic approaches to ameliorate obesity and diabetes have been proposed to affect the cellular targets of BA.

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Bile Acid Homeostasis in a Cholesterol 7α‐Hydroxylase and Sterol 27‐Hydroxylase Double Knockout Mouse Model

et al. 2019

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Bile acids (BAs) are diverse molecules that are synthesized from cholesterol in the liver. The synthesis of BAs has traditionally been shown to occur through two pathways. Cholesterol 7α‐hydroxylase (CYP7A1) performs the initial and rate‐limiting step in the classical pathway, and sterol 27‐hydroxylase (CYP27A1) initiates the hydroxylation of cholesterol in the alternative pathway. While the role of individual BA species as physiological detergents is relatively ubiquitous, their endocrine functions as signaling molecules and roles in disease pathogenesis have been emerging to be BA species–specific. In order to better understand the pharmacologic and toxicologic roles of individual BA species in an in vivo model, we created cholesterol 7α‐hydroxylase (Cyp7a1) and sterol 27‐hydroxylase (Cyp27a1) double knockout (DKO) mice by cross‐breeding single knockout mice (Cyp7a1–/– and Cyp27a1–/–). BA profiling and quantification by liquid chromatography–mass spectrometry of serum, gallbladder, liver, small intestine, and colon of wild‐type, Cyp7a1–/–, Cyp27a1–/–, and DKO mice showed that DKO mice exhibited a reduction of BAs in the plasma (45.9%), liver (60.2%), gallbladder (76.3%), small intestine (88.7%), and colon (93.6%), while maintaining a similar BA pool composition compared to wild‐type mice. The function of the farnesoid X receptor (FXR) in DKO mice was lower, revealed by decreased mRNA expression of well‐known FXR target genes, hepatic small heterodimer partner, and ileal fibroblast growth factor 15. However, response to FXR synthetic ligands was maintained in DKO mice as treatment with GW4064 resulted in similar changes in gene expression in all strains of mice. Conclusion: We provide a useful tool for studying the role of individual BAs in vivo; DKO mice have a significantly reduced BA pool, have a similar BA profile, and maintained response to FXR activation.

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The Immunomodulatory Role of Bile Acids

Cited by 68 publications

References 65 publications

Phosphorylation of Bcl-2 plays an important role in glycochenodeoxycholate-induced survival and chemoresistance in HCC

Phosphorylation of Bcl-2 plays an important role in glycochenodeoxycholate-induced survival and chemoresistance in HCC

The role of bile acids in metabolic regulation

Bile Acid Homeostasis in a Cholesterol 7α‐Hydroxylase and Sterol 27‐Hydroxylase Double Knockout Mouse Model

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