scholarly journals Mice with hepatocyte-specific FXR deficiency are resistant to spontaneous but susceptible to cholic acid-induced hepatocarcinogenesis

2016 ◽  
Vol 310 (5) ◽  
pp. G295-G302 ◽  
Author(s):  
Bo Kong ◽  
Yan Zhu ◽  
Guodong Li ◽  
Jessica A. Williams ◽  
Kyle Buckley ◽  
...  
Keyword(s):  
Cyclin D1 ◽  
Bile Acids ◽  
Cholic Acid ◽  
Liver Tumor ◽  
Liver Tumors ◽  
Tumor Formation ◽  
Farnesoid X Receptor ◽  
Whole Body ◽  
Wild Type ◽  
Depth Analysis

Farnesoid X receptor (FXR) belongs to the nuclear receptor superfamily with its endogenous ligands bile acids. Mice with whole body FXR deficiency develop liver tumors spontaneously, but the underlying mechanism is unclear. Moreover, it is unknown whether FXR deficiency in liver alone serves as a tumor initiator or promoter during liver carcinogenesis. This study aims to evaluate the effects of hepatocyte-specific FXR deficiency (FXRhep−/−) in liver tumor formation. The results showed that FXRhep−/− mice did not show spontaneous liver tumorigenesis with aging (up to 24 mo of age). Therefore FXRhep−/− mice were fed a bile acid (cholic acid)-containing diet alone or along with a liver tumor initiator, diethylnitrosamine (DEN). Thirty weeks later, no tumors were found in wild-type or FXRhep−/− mice without any treatment or with DEN only. However, with cholic acid, while only some wild-type mice developed tumors, all FXRhep−/− mice presented with severe liver injury and tumors. Interestingly, FXRhep−/− mouse livers increased basal expression of tumor suppressor p53 protein, apoptosis, and decreased basal cyclin D1 expression, which may prevent tumor development in FXRhep−/− mice. However, cholic acid feeding reversed these effects in FXRhep−/− mice, which is associated with an increased cyclin D1 and decreased cell cycle inhibitors. More in-depth analysis indicates that the increased in cell growth might result from disturbance of the MAPK and JAK/Stat3 signaling pathways. In conclusion, this study shows that hepatic FXR deficiency may only serve as a tumor initiator, and increased bile acids is required for tumor formation likely by promoting cell proliferation.

scholarly journals Investigating the Role of Farnesoid X Receptor in Heme Biosynthesis and Ductular Reaction

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A810-A811
Author(s):  
Angela E Dean ◽  
Emilian Jungwirth ◽  
Katrin Panzitt ◽  
Martin Wagner ◽  
Sayeepriyadarshini Anakk
Keyword(s):  
Gene Expression ◽  
Body Weight ◽  
Weight Ratio ◽  
Heme Biosynthesis ◽  
Farnesoid X Receptor ◽  
Whole Body ◽  
Wild Type ◽  
Body Weight Ratio ◽  
Ductular Reaction ◽  
Male And Female

Abstract Bile acids (BAs) have gained traction not just as emulsifiers of fat, but also as hormones. Nuclear receptor Farnesoid X receptor (FXR) is the master regulator of BAs and can also control glucose and lipid metabolism. We examined if FXR contributed towards heme biosynthesis and induction of a ductular reaction. Male and female whole body Fxr knockout (FxrKO) mice, as well as liver- and intestine-specific knockouts (LFxrKO and IFxrKO, respectively) were treated with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC, a ferrochelatase inhibitor) for two weeks. At the end of the two weeks, mice were fasted for four hours and euthanized. All groups of mice had lost a similar percentage of body weight when fed the DDC diet. However, female FxrKO mice had significantly increased liver to body weight ratio, while male FxrKO mice had significantly decreased liver to body weight ratio when fed the DDC diet compared with their wild type counterparts. Serum liver injury markers were analyzed and liver histology and changes in genes involved in the heme biosynthesis pathway were examined. Both male and female whole body FxrKO livers had decreased ductular reaction with minimal bile plugs (porphyrin accumulation) compared with their wild type counterparts. LFxrKO mice mimicked diminished ductular reaction, while IFxrKO mice exhibited severe ductular reaction similar to that of wild type mice, indicating that the ductular reaction is dependent on hepatic FXR. ChIP-Seq for FXR revealed binding peaks in the heme biosynthesis genes, Alas1, Alad, Uros, and Fech, suggesting that FXR may act as a transcription factor for these genes. Further investigation revealed that Pbgd gene expression was increased, while Fech gene expression was decreased in female FxrKO mice compared to wild type mice. In male mice, Pbgd, Uros, Urod, and Cpox gene expression was increased in the absence of Fxr. In conclusion, Fxr is necessary to mount a ductular reaction and plays a key role in heme biosynthesis in the liver.

scholarly journals Persistent hepatocyte apoptosis promotes tumorigenesis from diethylnitrosamine-transformed hepatocytes through increased oxidative stress, independent of compensatory liver regeneration

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yasutoshi Nozaki ◽  
Hayato Hikita ◽  
Satoshi Tanaka ◽  
Kenji Fukumoto ◽  
Makiko Urabe ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hepatocellular Carcinoma ◽  
Chronic Hepatitis ◽  
Liver Regeneration ◽  
Liver Tumors ◽  
Tumor Formation ◽  
Transformed Cells ◽  
Wild Type ◽  
Hepatocyte Apoptosis ◽  
Chronic Liver Injury

AbstractHepatocellular carcinoma highly occurs in chronic hepatitis livers, where hepatocyte apoptosis is frequently detected. Apoptosis is a mechanism that eliminates mutated cells. Hepatocyte apoptosis induces compensatory liver regeneration, which is believed to contribute to tumor formation. Hepatocyte-specific Mcl-1 knockout mice (Mcl-1Δhep mice) developed persistent hepatocyte apoptosis and compensatory liver regeneration with increased oxidative stress in adulthood but had not yet developed hepatocyte apoptosis at the age of 2 weeks. When diethylnitrosamine (DEN) was administered to 2-week-old Mcl-1Δhep mice, multiple liver tumors were formed at 4 months, while wild-type mice did not develop any tumors. These tumors contained the B-Raf V637E mutation, indicating that DEN-initiated tumorigenesis was promoted by persistent hepatocyte apoptosis. When N-acetyl-L-cysteine was given from 6 weeks of age, DEN-administered Mcl-1Δhep mice had reduced oxidative stress and suppressed tumorigenesis in the liver but showed no changes in hepatocyte apoptosis or proliferation. In conclusion, enhanced tumor formation from DEN-transformed hepatocytes by persistent hepatocyte apoptosis is mediated by increased oxidative stress, independent of compensatory liver regeneration. For patients with livers harboring transformed cells, the control of oxidative stress may suppress hepatocarcinogenesis based on chronic liver injury.

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.

An Evaluation of the Human Relevance of the Liver Tumors Observed in Female Mice Treated With Permethrin Based on Mode of Action

2020 ◽  
Vol 175 (1) ◽  
pp. 50-63 ◽  
Author(s):  
Miwa Kondo ◽  
Hiroko Kikumoto ◽  
Thomas G Osimitz ◽  
Samuel M Cohen ◽  
Brian G Lake ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Dna Synthesis ◽  
Liver Tumor ◽  
Mode Of Action ◽  
Mouse Liver ◽  
Liver Tumors ◽  
Tumor Formation ◽  
Human Hepatocytes ◽  
Mrna Levels ◽  
Mouse Hepatocytes

Abstract In 2-year studies, the nongenotoxic pyrethroid insecticide permethrin produced hepatocellular tumors in CD-1 mice but not in Wistar rats. Recently, we demonstrated that the mode of action (MOA) for mouse liver tumor formation by permethrin involves activation of the peroxisome proliferator-activated receptor alpha (PPARα), resulting in a mitogenic effect. In the present study, the effects of permethrin and 2 major permethrin metabolites, namely 3-phenoxybenzoic acid and trans-dichlorochrysanthemic acid, on cytochrome P450 mRNA levels and cell proliferation (determined as replicative DNA synthesis) were evaluated in cultured CD-1 mouse, Wistar rat, and human hepatocytes. Permethrin and 3-phenoxybenzoic acid induced CYP4A mRNA levels in both mouse and human hepatocytes, with trans-dichlorochrysanthemic acid also increasing CYP4A mRNA levels in mouse hepatocytes. 3-Phenoxybenzoic acid induced CYP4A mRNA levels in rat hepatocytes, with trans-dichlorochrysanthemic acid increasing both CYP4A mRNA levels and replicative DNA synthesis. Permethrin, 3-phenoxybenzoic acid, and trans-dichlorochrysanthemic acid stimulated replicative DNA synthesis in mouse hepatocytes but not in human hepatocytes, demonstrating that human hepatocytes are refractory to the mitogenic effects of permethrin and these 2 metabolites. Thus, although some of the key (eg, PPARα activation) and associative (eg, CYP4A induction) events in the established MOA for permethrin-induced mouse liver tumor formation could occur in human hepatocytes at high doses of permethrin, 3-phenoxybenzoic acid, and/or trans-dichlorochrysanthemic acid, increased cell proliferation (an essential step in carcinogenesis by nongenotoxic PPARα activators) was not observed. These results provide additional evidence that the established MOA for permethrin-induced mouse liver tumor formation is not plausible for humans.

scholarly journals Potential of therapeutic bile acids in the treatment of neonatal Hyperbilirubinemia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lori W. E. van der Schoor ◽  
Henkjan J. Verkade ◽  
Anna Bertolini ◽  
Sanne de Wit ◽  
Elvira Mennillo ◽  
...  
Keyword(s):  
Bile Acids ◽  
Treatment Options ◽  
Preventive Treatment ◽  
Neonatal Hyperbilirubinemia ◽  
Farnesoid X Receptor ◽  
Neurological Damage ◽  
Obeticholic Acid ◽  
Protein Levels ◽  
Gunn Rats ◽  
Plasma Bilirubin

AbstractNeonatal hyperbilirubinemia or jaundice is associated with kernicterus, resulting in permanent neurological damage or even death. Conventional phototherapy does not prevent hyperbilirubinemia or eliminate the need for exchange transfusion. Here we investigated the potential of therapeutic bile acids ursodeoxycholic acid (UDCA) and obeticholic acid (OCA, 6-α-ethyl-CDCA), a farnesoid-X-receptor (FXR) agonist, as preventive treatment options for neonatal hyperbilirubinemia using the hUGT1*1 humanized mice and Ugt1a-deficient Gunn rats. Treatment of hUGT1*1 mice with UDCA or OCA at postnatal days 10–14 effectively decreased bilirubin in plasma (by 82% and 62%) and brain (by 72% and 69%), respectively. Mechanistically, our findings indicate that these effects are mediated through induction of protein levels of hUGT1A1 in the intestine, but not in liver. We further demonstrate that in Ugt1a-deficient Gunn rats, UDCA but not OCA significantly decreases plasma bilirubin, indicating that at least some of the hypobilirubinemic effects of UDCA are independent of UGT1A1. Finally, using the synthetic, non-bile acid, FXR-agonist GW4064, we show that some of these effects are mediated through direct or indirect activation of FXR. Together, our study shows that therapeutic bile acids UDCA and OCA effectively reduce both plasma and brain bilirubin, highlighting their potential in the treatment of neonatal hyperbilirubinemia.

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.

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