Farnesoid X Receptor Mediates Tumor Immune Evasion by Targeting PD-L1 Induced by a Novel Bile Acid in Hepatocellular Carcinoma

2021 ◽  
Author(s):  
Yihang Gong ◽  
Kun Liao ◽  
Yunfei Qin ◽  
Xianzhi Liu ◽  
Kaining Zeng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Bile Acid ◽  
Immune Evasion ◽  
Farnesoid X Receptor ◽  
Tumor Immune Evasion

scholarly journals ERRFI1 induces apoptosis of hepatocellular carcinoma cells in response to tryptophan deficiency

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Mingqing Cui ◽  
Dan Liu ◽  
Wujun Xiong ◽  
Yugang Wang ◽  
Jun Mi
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Growth ◽  
Cancer Cells ◽  
Immune Evasion ◽  
Breast Cancer Cells ◽  
Carcinoma Cells ◽  
Tryptophan Metabolism ◽  
Tumor Immune Evasion ◽  
Induced Apoptosis ◽  
Hcc Cells

AbstractTryptophan metabolism is an essential regulator of tumor immune evasion. However, the effect of tryptophan metabolism on cancer cells remains largely unknown. Here, we find that tumor cells have distinct responses to tryptophan deficiency in terms of cell growth, no matter hepatocellular carcinoma (HCC) cells, lung cancer cells, or breast cancer cells. Further study shows that ERRFI1 is upregulated in sensitive HCC cells, but not in resistant HCC cells, in response to tryptophan deficiency, and ERRFI1 expression level positively correlates with HCC patient overall survival. ERRFI1 knockdown recovers tryptophan deficiency-suppressed cell growth of sensitive HCC cells. In contrast, ERRFI1 overexpression sensitizes resistant HCC cells to tryptophan deficiency. Moreover, ERRFI1 induces apoptosis by binding PDCD2 in HCC cells, PDCD2 knockdown decreases the ERRFI1-induced apoptosis in HCC cells. Thus, we conclude that ERRFI1-induced apoptosis increases the sensitivity of HCC cells to tryptophan deficiency and ERRFI1 interacts with PDCD2 to induce apoptosis in HCC cells.

scholarly journals Role of Bile Acids in the Regulation of Food Intake, and Their Dysregulation in Metabolic Disease

Nutrients ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 1104
Author(s):  
Cong Xie ◽  
Weikun Huang ◽  
Richard L. Young ◽  
Karen L. Jones ◽  
Michael Horowitz ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Peptide Yy ◽  
Glycogen Synthesis ◽  
Hormone Secretion ◽  
Gastrointestinal Hormones ◽  
Farnesoid X Receptor ◽  
Gastrointestinal Hormone ◽  
Bile Acid Sequestrants

Bile acids are cholesterol-derived metabolites with a well-established role in the digestion and absorption of dietary fat. More recently, the discovery of bile acids as natural ligands for the nuclear farnesoid X receptor (FXR) and membrane Takeda G-protein-coupled receptor 5 (TGR5), and the recognition of the effects of FXR and TGR5 signaling have led to a paradigm shift in knowledge regarding bile acid physiology and metabolic health. Bile acids are now recognized as signaling molecules that orchestrate blood glucose, lipid and energy metabolism. Changes in FXR and/or TGR5 signaling modulates the secretion of gastrointestinal hormones including glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), hepatic gluconeogenesis, glycogen synthesis, energy expenditure, and the composition of the gut microbiome. These effects may contribute to the metabolic benefits of bile acid sequestrants, metformin, and bariatric surgery. This review focuses on the role of bile acids in energy intake and body weight, particularly their effects on gastrointestinal hormone secretion, the changes in obesity and T2D, and their potential relevance to the management of metabolic disorders.

scholarly journals Role of FXR in Bile Acid and Metabolic Homeostasis in NASH: Pathogenetic Concepts and Therapeutic Opportunities

2021 ◽  
Author(s):  
Richard Radun ◽  
Michael Trauner
Keyword(s):  
Liver Disease ◽  
Bile Acid ◽  
Enterohepatic Circulation ◽  
Therapeutic Potential ◽  
Farnesoid X Receptor ◽  
Metabolic Homeostasis ◽  
Nonalcoholic Fatty Liver ◽  
Metabolic Dysregulation ◽  
Attractive Therapeutic Target

AbstractNonalcoholic fatty liver disease (NAFLD) has become the most prevalent cause of liver disease, increasingly contributing to the burden of liver transplantation. In search for effective treatments, novel strategies addressing metabolic dysregulation, inflammation, and fibrosis are continuously emerging. Disturbed bile acid (BA) homeostasis and microcholestasis via hepatocellular retention of potentially toxic BAs may be an underappreciated factor in the pathogenesis of NAFLD and nonalcoholic steatohepatitis (NASH) as its progressive variant. In addition to their detergent properties, BAs act as signaling molecules regulating cellular homeostasis through interaction with BA receptors such as the Farnesoid X receptor (FXR). Apart from being a key regulator of BA metabolism and enterohepatic circulation, FXR regulates metabolic homeostasis and has immune-modulatory effects, making it an attractive therapeutic target in NAFLD/NASH. In this review, the molecular basis and therapeutic potential of targeting FXR with a specific focus on restoring BA and metabolic homeostasis in NASH is summarized.

scholarly journals Lactobacillus delbrueckii Interfere With Bile Acid Enterohepatic Circulation to Regulate Cholesterol Metabolism of Growing–Finishing Pigs via Its Bile Salt Hydrolase Activity

2020 ◽  
Vol 7 ◽  
Author(s):  
Gaifeng Hou ◽  
Wei Peng ◽  
Liangkai Wei ◽  
Rui Li ◽  
Yong Yuan ◽  
...  
Keyword(s):  
Bile Acid ◽  
Enterohepatic Circulation ◽  
Cholesterol Metabolism ◽  
Binding Protein ◽  
Density Lipoprotein ◽  
Lactobacillus Delbrueckii ◽  
Farnesoid X Receptor ◽  
Bile Salt Hydrolase ◽  
Lipoprotein Receptor ◽  
Density Lipoprotein Receptor

Microbiota-targeted therapies for hypercholesterolemia get more and more attention and are recognized as an effective strategy for preventing and treating cardiovascular disease. The experiment was conducted to investigate the cholesterol-lowering mechanism of Lactobacillus delbrueckii in a pig model. Twelve barrows (38.70 ± 5.33 kg) were randomly allocated to two groups and fed corn–soybean meal diets with either 0% (Con) or 0.1% Lactobacillus delbrueckii (Con + LD) for 28 days. L. delbrueckii–fed pigs had lower serum contents of total cholesterol (TC), total bile acids (TBAs), and triglyceride, but higher fecal TC and TBA excretion. L. delbrueckii treatment increased ileal Lactobacillus abundance and bile acid (BA) deconjugation and affected serum and hepatic BA composition. Dietary L. delbrueckii downregulated the gene expression of ileal apical sodium-dependent bile acid transporter (ASBT) and ileal bile acid binding protein (IBABP), and hepatic farnesoid X receptor (FXR), fibroblast growth factor (FGF19), and small heterodimer partner (SHP), but upregulated hepatic high-density lipoprotein receptor (HDLR), low-density lipoprotein receptor (LDLR), sterol regulatory element binding protein-2 (SREBP-2), and cholesterol-7α hydroxylase (CYP7A1) expression. Our results provided in vivo evidence that L. delbrueckii promote ileal BA deconjugation with subsequent fecal TC and TBA extraction by modifying ileal microbiota composition and induce hepatic BA neosynthesis via regulating gut–liver FXR–FGF19 axis.

scholarly journals Farnesoid X receptor induces Takeda G-protein receptor 5 cross-talk to regulate bile acid synthesis and hepatic metabolism

2017 ◽  
Vol 292 (26) ◽  
pp. 11055-11069 ◽  
Author(s):  
Preeti Pathak ◽  
Hailiang Liu ◽  
Shannon Boehme ◽  
Cen Xie ◽  
Kristopher W. Krausz ◽  
...  
Keyword(s):  
Bile Acid ◽  
G Protein ◽  
Cross Talk ◽  
Hepatic Metabolism ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Farnesoid X Receptor ◽  
Protein Receptor

Role of nuclear receptors and hepatocyte-enriched transcription factors for Ntcp repression in biliary obstruction in mouse liver

2005 ◽  
Vol 289 (5) ◽  
pp. G798-G805 ◽  
Author(s):  
Gernot Zollner ◽  
Martin Wagner ◽  
Peter Fickert ◽  
Andreas Geier ◽  
Andrea Fuchsbichler ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Bile Acid ◽  
Dna Binding ◽  
Nuclear Receptors ◽  
Farnesoid X Receptor ◽  
Acid Uptake ◽  
Mrna Levels ◽  
Uptake System ◽  
Duct Ligation

Expression of the main hepatic bile acid uptake system, the Na+-taurocholate cotransporter (Ntcp), is downregulated during cholestasis. Bile acid-induced, farnesoid X receptor (FXR)-mediated induction of the nuclear repressor short heterodimer partner (SHP) has been proposed as a key mechanism reducing Ntcp expression. However, the role of FXR and SHP or other nuclear receptors and hepatocyte-enriched transcription factors in mediating Ntcp repression in obstructive cholestasis is unclear. FXR knockout (FXR−/−) and wild-type (FXR+/+) mice were subjected to common bile duct ligation (CBDL). Cholic acid (CA)-fed and LPS-treated FXR−/− and FXR+/+ mice were studied for comparison. mRNA levels of Ntcp and SHP and nuclear protein levels of hepatocyte nuclear factor (HNF)-1α, HNF-3β, HNF-4α, retinoid X receptor (RXR)-α, and retinoic acid receptor (RAR)-α and their DNA binding were assessed. Hepatic cytokine mRNA levels were also measured. CBDL and CA led to Ntcp repression in FXR+/+, but not FXR−/−, mice, whereas LPS reduced Ntcp expression in both genotypes. CBDL and LPS but not CA induced cytokine expression and reduced levels of HNF-1α, HNF-3β, HNF-4α, RXRα, and RARα to similar extents in FXR+/+ and FXR−/−. DNA binding of these transactivators was unaffected by CA in FXR+/+ mice but was markedly reduced in FXR−/− mice. In conclusion, Ntcp repression by CBDL and CA is mediated by accumulating bile acids via FXR and does not depend on cytokines, whereas Ntcp repression by LPS is independent of FXR. Reduced levels of HNF-1α, RXRα, and RARα in CBDL FXR−/− mice and reduced DNA binding in CA-fed FXR−/− mice, despite unchanged Ntcp levels, indicate that these factors may have a minor role in regulation of mouse Ntcp during cholestasis.

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