scholarly journals Bile Acids Induce IQ Containing GTPase Activating Protein 1 to Alleviate Liver Injury

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A498-A498
Author(s):  
Anushna Sen ◽  
Hanna Erickson ◽  
Sayeepriyadarshini Anakk
Keyword(s):  
Gene Expression ◽  
Bile Acid ◽  
Liver Injury ◽  
Bile Acids ◽  
Mapk Signaling ◽  
Serum Bile Acid ◽  
Dependent Manner ◽  
Male Mice ◽  
Wild Type ◽  
Junction Protein

Abstract Bile acids (BA) are cholesterol metabolites synthesized in the liver. In addition to their role as detergents, bile acids can function as signaling molecules via the activation of nuclear and G-protein coupled receptors, FXR and TGR5. BA signaling is associated with inflammation, cell proliferation, as well as apoptosis in the liver. Excessive accumulation of bile acids in the liver (cholestasis) is observed in many diseased states. We found that the scaffold protein IQGAP1 was induced in mouse models of cholestasis and in patients. In vitro BA treatment of liver cell-line, HepG2 also induced IQGAP1 in a dose-dependent manner. To investigate the role of this IQGAP1 induction, we fed wild-type male mice 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet for 3days, 1week, and 2weeks. Serum bile acid and hepatic IQGAP1 induction increased concomitantly with time. We next treated Iqgap1-/- male mice similarly with DDC and found a 3-fold increase in serum bile acid levels compared to treated wild-type mice. Liver injury markers ALT, AST, and bilirubin were also increased. Although Iqgap1-/- mice had similar gene expression of key BA regulators, Fxr and Shp as wild-type mice, the alteration in expression of BA transporters and reduced cell-cell junction protein levels may contribute to the elevated BAs levels. We quantified gene expression of pro-inflammatory and proliferative mediators using qRT-PCR and examined the liver histology with immuno-staining. We found Iqgap1-/- livers expressed increased pro-inflammatory mediators and proliferative genes like Il-6 and cyclin D1 along with MAPK signaling targets, Fos and Egr-1. To further examine how IQGAP1 functions as a mediator of bile acid signaling, we have generated IQGAP1 domain deleted constructs and are examining their protein-protein interactions with Mass Spec. Based on our results, IQGAP1 induction subsequent to accumulation of BAs is protective against injury in the liver.

Abstract 296: Decreased Hepatic Avpr1a Gene Expression and Elevated Serum Bile Acid in Mouse Model of Metabolic Syndrome

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Xiaoya Ma ◽  
Peter F Bodary
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Bile Acid ◽  
Bile Acids ◽  
Serum Bile Acid ◽  
Hepatic Gene Expression ◽  
Serum Bile Acids ◽  
Kk Mice ◽  
The Metabolic Syndrome

The KK/HIJ mouse has been demonstrated to have polygenic obesity and insulin resistance and serve as a model of metabolic syndrome. From microarray studies in this mouse strain, we observed hepatic gene expression of arginine vasopressin receptor 1A (Avpr1a) as the most differentially elevated gene in the liver following 3-week of voluntary wheel running activity. Subsequent studies validated that hepatic Avpr1a gene expression is significantly upregulated following voluntary activity and also highly suppressed (4 to 8-fold) in 2 independent models of insulin resistance (including obesity and lipoatrophic models). Although Avpr1a is highly abundant in the liver, its physiologic role is not well described. One proposed role for hepatic Avpr1a is mediation of vasopressin-induced bile acid secretion. To further evaluate the relationship between hepatic Avpr1a and bile acid homeostasis, we determined the age-related change in these variables in female KK mice. To investigate, adipose tissue, liver and serum were collected from female KK mice from before sexual maturity (PRE: 4.5 weeks old, n=9) and after sexual maturation (POST: 6 to 30 weeks old, n=12). Consistent with previous studies using this obesity-prone strain, we observed a robust increase in adiposity with age despite a standard rodent chow diet. RT-PCR studies of hepatic gene expression revealed a 53% lower Avpr1a in POST compared to PRE mice (p<0.00001). In parallel with the drop in hepatic Avpr1a gene expression was an increase in serum bile acids (PRE: 26.56± 9.98μmol/L; POST: 39.40± 9.63μmol/L; p<0.01). A negative correlation was evident between hepatic Avpr1a gene expression and serum bile acid level (R= -0.51). The change in Avpr1a and bile acids was pronounced at the age of onset of estrous cycling. In conclusion, female KK mice have a significant increase in fat mass with age in parallel with an elevation of serum bile acids and downregulation of hepatic Avpr1a gene expression. We propose that suppression of hepatic Avpr1a increases hydrophobic bile acids in the liver and serum and promotes hepatic inflammation, contributing to symptoms of the metabolic syndrome.

scholarly journals Regulation of expression of human intestinal bile acid-binding protein in Caco-2 cells

1998 ◽  
Vol 330 (1) ◽  
pp. 261-265 ◽  
Author(s):  
Tatsuo KANDA ◽  
Laurent FOUCAND ◽  
Yuichi NAKAMURA ◽  
Isabelle NIOT ◽  
Philippe BESNARD ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bile Acid ◽  
Western Blot ◽  
Bile Acids ◽  
Transport System ◽  
Binding Protein ◽  
Dependent Manner ◽  
Acid Binding Protein ◽  
Bile Acid Binding ◽  
Active Transport System

Molecular mechanisms of the bile acid active transport system in the ileal enterocytes remain unknown. We examined whether bile acids affect human enterocyte gene expression of intestinal bile acid-binding protein (I-BABP), a component of this transport system. Differentiated Caco-2 cells were incubated in the presence of human bile, bile acids or other lipids. The level of I-BABP expression was evaluated by Northern and Western blot analyses. A 24 h incubation of Caco-2 cells in a medium containing either bile or bile acids resulted in a remarkable 7.5-fold increase in the I-BABP mRNA level over the control level. Neither cholesterol, palmitic acid, phosphatidylcholine nor cholestyramine treated bile showed any difference in I-BABP mRNA expression from the control. Bile acid treatment increased the level of I-BABP mRNA in Caco-2 cells in a time- and dose-dependent manner. Western blot analysis showed that this induction led to increase in cytosolic I-BABP. Chenodeoxycholic acid and deoxycholic acid showed greater induction effects than other hydrophilic bile acids, including their own glycine conjugates. Pretreatment by actinomycin D or cycloheximide completely inhibited the up-regulation of I-BABP expression by bile acid. Bile acids, especially lipophilic bile acids, increase the I-BABP expression in Caco-2-cells, suggesting that luminal bile acids play an important role in regulating the I-BABP gene expression.

scholarly journals Ostα depletion protects liver from oral bile acid load

2011 ◽  
Vol 301 (3) ◽  
pp. G574-G579 ◽  
Author(s):  
Carol J. Soroka ◽  
Heino Velazquez ◽  
Albert Mennone ◽  
Nazzareno Ballatori ◽  
James L. Boyer
Keyword(s):  
Bile Acid ◽  
Liver Injury ◽  
Bile Acids ◽  
Cholic Acid ◽  
Fecal Excretion ◽  
Wild Type ◽  
Duct Ligation ◽  
Acid Load ◽  
Almost All ◽  
Deficient Mice

Bile acid homeostasis is tightly maintained through interactions between the liver, intestine, and kidney. During cholestasis, the liver is incapable of properly clearing bile acids from the circulation, and alternative excretory pathways are utilized. In obstructive cholestasis, urinary elimination is often increased, and this pathway is further enhanced after bile duct ligation in mice that are genetically deficient in the heteromeric, basolateral organic solute transporter alpha-beta (Ostα-Ostβ). In this study, we examined renal and intestinal function in Ostα-deficient and wild-type mice in a model of bile acid overload. After 1% cholic acid feeding, Ostα-deficient mice had significantly lower serum ALT levels compared with wild-type controls, indicating partial protection from liver injury. Urinary clearance of bile acids, but not clearance of [3H]inulin, was significantly higher in cholic acid-fed Ostα-deficient mice compared with wild-type mice but was not sufficient to account for the protection. Fecal excretion of bile acids over the 5 days of cholic acid feeding was responsible for almost all of the bile acid loss in Ostα-deficient mice, suggesting that intestinal losses of bile acids accounted for the protection from liver injury. Thus fecal loss of bile acids after bile acid overload reduced the need for the kidney to filter and excrete the excess bile acids. In conclusion, Ostα-deficient mice efficiently eliminate excess bile acids via the feces. Inhibition of intestinal bile acid absorption might be an effective therapeutic target in early stages of cholestasis when bile acids are still excreted into bile.

Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD

Gut ◽  
2017 ◽  
Vol 67 (10) ◽  
pp. 1881-1891 ◽  
Author(s):  
Na Jiao ◽  
Susan S Baker ◽  
Adrian Chapa-Rodriguez ◽  
Wensheng Liu ◽  
Colleen A Nugent ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bile Acid ◽  
Bile Acids ◽  
Gut Microbiome ◽  
High Fat Diet ◽  
Serum Bile Acid ◽  
Fibroblast Growth ◽  
High Fat ◽  
Liver Gene ◽  
Secondary Bile Acids

ObjectiveBile acids are regulators of lipid and glucose metabolism, and modulate inflammation in the liver and other tissues. Primary bile acids such as cholic acid and chenodeoxycholic acid (CDCA) are produced in the liver, and converted into secondary bile acids such as deoxycholic acid (DCA) and lithocholic acid by gut microbiota. Here we investigated the possible roles of bile acids in non-alcoholic fatty liver disease (NAFLD) pathogenesis and the impact of the gut microbiome on bile acid signalling in NAFLD.DesignSerum bile acid levels and fibroblast growth factor 19 (FGF19), liver gene expression profiles and gut microbiome compositions were determined in patients with NAFLD, high-fat diet-fed rats and their controls.ResultsSerum concentrations of primary and secondary bile acids were increased in patients with NAFLD. In per cent, the farnesoid X receptor (FXR) antagonistic DCA was increased, while the agonistic CDCA was decreased in NAFLD. Increased mRNA expression for cytochrome P450 7A1, Na+-taurocholate cotransporting polypeptide and paraoxonase 1, no change in mRNA expression for small heterodimer partner and bile salt export pump, and reduced serum FGF19 were evidence of impaired FXR and fibroblast growth factor receptor 4 (FGFR4)-mediated signalling in NAFLD. Taurine and glycine metabolising bacteria were increased in the gut of patients with NAFLD, reflecting increased secondary bile acid production. Similar changes in liver gene expression and the gut microbiome were observed in high-fat diet-fed rats.ConclusionsThe serum bile acid profile, the hepatic gene expression pattern and the gut microbiome composition consistently support an elevated bile acid production in NAFLD. The increased proportion of FXR antagonistic bile acid explains, at least in part, the suppression of hepatic FXR-mediated and FGFR4-mediated signalling. Our study suggests that future NAFLD intervention may target the components of FXR signalling, including the bile acid converting gut microbiome.

scholarly journals Arbutin Alleviates the Liver Injury of α-Naphthylisothiocyanate-induced Cholestasis Through Farnesoid X Receptor Activation

2021 ◽  
Vol 9 ◽  
Author(s):  
Peijie Wu ◽  
Ling Qiao ◽  
Han Yu ◽  
Hui Ming ◽  
Chao Liu ◽  
...  
Keyword(s):  
Bile Acid ◽  
Liver Injury ◽  
Protective Effect ◽  
Bile Acids ◽  
Liver Toxicity ◽  
Enterohepatic Circulation ◽  
Receptor Activation ◽  
Farnesoid X Receptor ◽  
Bile Acid Metabolism ◽  
Cholestatic Diseases

Cholestasis is a kind of stressful syndrome along with liver toxicity, which has been demonstrated to be related to fibrosis, cirrhosis, even cholangiocellular or hepatocellular carcinomas. Cholestasis usually caused by the dysregulated metabolism of bile acids that possess high cellular toxicity and synthesized by cholesterol in the liver to undergo enterohepatic circulation. In cholestasis, the accumulation of bile acids in the liver causes biliary and hepatocyte injury, oxidative stress, and inflammation. The farnesoid X receptor (FXR) is regarded as a bile acid–activated receptor that regulates a network of genes involved in bile acid metabolism, providing a new therapeutic target to treat cholestatic diseases. Arbutin is a glycosylated hydroquinone isolated from medicinal plants in the genus Arctostaphylos, which has a variety of potentially pharmacological properties, such as anti-inflammatory, antihyperlipidemic, antiviral, antihyperglycemic, and antioxidant activity. However, the mechanistic contributions of arbutin to alleviate liver injury of cholestasis, especially its role on bile acid homeostasis via nuclear receptors, have not been fully elucidated. In this study, we demonstrate that arbutin has a protective effect on α-naphthylisothiocyanate–induced cholestasis via upregulation of the levels of FXR and downstream enzymes associated with bile acid homeostasis such as Bsep, Ntcp, and Sult2a1, as well as Ugt1a1. Furthermore, the regulation of these functional proteins related to bile acid homeostasis by arbutin could be alleviated by FXR silencing in L-02 cells. In conclusion, a protective effect could be supported by arbutin to alleviate ANIT-induced cholestatic liver toxicity, which was partly through the FXR pathway, suggesting arbutin may be a potential chemical molecule for the cholestatic disease.

Potential Implications for Monitoring Serum Bile Acid Profiles in Circulation with Serum Proteome for Carbon Tetrachloride-Induced Liver Injury/Regeneration Model in Mice

2010 ◽  
Vol 9 (9) ◽  
pp. 4490-4500 ◽  
Author(s):  
Takashi Shimada ◽  
Tsuyoshi Nakanishi ◽  
Atsuhiko Toyama ◽  
Satoshi Yamauchi ◽  
Atsuhiro Kanzaki ◽  
...  
Keyword(s):  
Bile Acid ◽  
Carbon Tetrachloride ◽  
Liver Injury ◽  
Serum Bile Acid ◽  
Serum Proteome ◽  
Bile Acid Profiles

TGR5 signaling mitigates parenteral nutrition-associated liver disease

2020 ◽  
Vol 318 (2) ◽  
pp. G322-G335
Author(s):  
Kent A. Willis ◽  
Charles K. Gomes ◽  
Prahlad Rao ◽  
Dejan Micic ◽  
E. Richard Moran ◽  
...  
Keyword(s):  
Liver Disease ◽  
Bile Acid ◽  
Parenteral Nutrition ◽  
Bile Acids ◽  
G Protein ◽  
Prolonged Exposure ◽  
Serum Bile Acid ◽  
Immune Functions ◽  
Protein Receptor ◽  
Secondary Bile Acids

Bile acid receptors regulate the metabolic and immune functions of circulating enterohepatic bile acids. This process is disrupted by administration of parenteral nutrition (PN), which may induce progressive hepatic injury for unclear reasons, especially in the newborn, leading to PN-associated liver disease. To explore the role of bile acid signaling on neonatal hepatic function, we initially observed that Takeda G protein receptor 5 (TGR5)-specific bile acids were negatively correlated with worsening clinical disease markers in the plasma of human newborns with prolonged PN exposure. To test our resulting hypothesis that TGR5 regulates critical liver functions to PN exposure, we used TGR5 receptor deficient mice (TGR5−/−). We observed PN significantly increased liver weight, cholestasis, and serum hepatic stress enzymes in TGR5−/− mice compared with controls. Mechanistically, PN reduced bile acid synthesis genes in TGR5−/−. Serum bile acid composition revealed that PN increased unconjugated primary bile acids and secondary bile acids in TGR5−/− mice, while increasing conjugated primary bile acid levels in TGR5-competent mice. Simultaneously, PN elevated hepatic IL-6 expression and infiltrating macrophages in TGR5−/− mice. However, the gut microbiota of TGR5−/− mice compared with WT mice following PN administration displayed highly elevated levels of Bacteroides and Parabacteroides, and possibly responsible for the elevated levels of secondary bile acids in TGR5−/− animals. Intestinal bile acid transporters expression was unchanged. Collectively, this suggests TGR5 signaling specifically regulates fundamental aspects of liver bile acid homeostasis during exposure to PN. Loss of TGR5 is associated with biochemical evidence of cholestasis in both humans and mice on PN. NEW & NOTEWORTHY Parenteral nutrition is associated with deleterious metabolic outcomes in patients with prolonged exposure. Here, we demonstrate that accelerated cholestasis and parental nutrition-associated liver disease (PNALD) may be associated with deficiency of Takeda G protein receptor 5 (TGR5) signaling. The microbiome is responsible for production of secondary bile acids that signal through TGR5. Therefore, collectively, these data support the hypothesis that a lack of established microbiome in early life or under prolonged parenteral nutrition may underpin disease development and PNALD.

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