• ADPKD
• T-cell
• drug induced liver injury
• hypersensitivity
• idiosyncratic
• tolvaptan

• Tolvaptan/therapeutic use
• Chemical and Drug Induced Liver Injury/etiology
• Humans
• Polycystic Kidney, Autosomal Dominant/drug therapy
• Antidiuretic Hormone Receptor Antagonists/therapeutic use
• Animals
• Risk Factors

• ERK1/2
• Estradiol 17β-D-glucuronide
• Mrp2
• NADPH oxidase
• Reactive oxygen species
• p38MAPK

• Animals
• NADPH Oxidases/metabolism
• Reactive Oxygen Species/metabolism
• Rats
• Hepatocytes/metabolism
• Hepatocytes/drug effects
• Estradiol/pharmacology
• Estradiol/metabolism
• Estradiol/analogs & derivatives
• Female
• Cholestasis/chemically induced
• Cholestasis/metabolism
• Cholestasis/pathology
• Rats, Wistar
• Acetophenones/pharmacology
• Oxidative Stress/drug effects
• Acetylcysteine/pharmacology
• p38 Mitogen-Activated Protein Kinases/metabolism
• Multidrug Resistance-Associated Proteins/metabolism
• MAP Kinase Signaling System/drug effects
• Cells, Cultured
• Antioxidants/pharmacology
• Antioxidants/metabolism
• Cholestasis, Intrahepatic
• Pregnancy Complications
• ATP-Binding Cassette Transporters

• Humans
• Ursodeoxycholic Acid/therapeutic use
• Ursodeoxycholic Acid/pharmacology
• Cholestasis/drug therapy
• Liver Diseases/drug therapy
• Chemical and Drug Induced Liver Injury/etiology
• Necrosis/drug therapy
• Liver

• Cycloserine
• Dextromethorphan
• Minocycline
• NMDA
• Obesity
• Progesterone
• Serotonin
• d-Aspartate

• Female
• Mice
• Animals
• N-Methylaspartate/pharmacology
• Receptors, N-Methyl-D-Aspartate/metabolism
• Serotonin/metabolism
• Progesterone/pharmacology
• Peanut Oil/metabolism
• Peanut Oil/pharmacology
• Peanut Oil/therapeutic use
• Obesity/drug therapy
• Obesity/metabolism
• Hypothalamus
• Insulins/metabolism
• Insulins/pharmacology
• Insulins/therapeutic use
• gamma-Aminobutyric Acid

• Cancer
• Hepatocellular carcinoma
• Lipid
• Lipidomics
• Metabolism

• Antioxidants
• CNS and Systemic oxidative stress
• Central nervous system
• Hepatic encephalopathy

Nonalcoholic fatty liver disease (NAFLD), characterized by ectopic fat accumulation in hepatocytes, is closely linked to insulin resistance and is the most frequent complication of type 2 diabetes mellitus (T2DM). One of the features connecting NAFLD, insulin resistance and T2DM is cellular oxidative stress. Oxidative stress refers to a redox imbalance due to an inequity between the capacity of production and the elimination of reactive oxygen species (ROS). One of the major cellular ROS sources is NADPH oxidase enzymes (NOX-es). In physiological conditions, NOX-es produce ROS purposefully in a timely and spatially regulated manner and are crucial regulators of various cellular events linked to metabolism, receptor signal transmission, proliferation and apoptosis. In contrast, dysregulated NOX-derived ROS production is related to the onset of diverse pathologies. This review provides a synopsis of current knowledge concerning NOX enzymes as connective elements between NAFLD, insulin resistance and T2DM and weighs their potential relevance as pharmacological targets to alleviate fatty liver disease.

• NADPH oxidase
• NAFLD
• NOX
• ROS
• diabetes
• hepatosteatosis
• insulin resistance
• nonalcoholic fatty liver disease
• oxidative stress
• reactive oxygen species

• 189003 Swiss National Science Foundation

Bile acids (BAs) have long been known to facilitate digestion, transport, and absorption of lipids in the small intestine as well as regulate host lipid metabolic homeostasis. However, excessive BAs may lead to long-term damage to tissue. Also, it is unknown whether different levels of porcine BAs supplementation could improve performance, host metabolism, intestinal functions in laying hens. Hence, this study was aimed to investigate the potential effects of BAs addition on laying performance, egg quality, blood parameters, organ indexes, and intestinal histopathology of hens in the late phase. A total of 300 58-week-old Hy-line Gray hens were randomly divided into five groups which fed a basal diet (control) or basal diets supplemented with 60, 300, 600, and 3,000 mg/kg BAs for 56 days. Compared with the control group, no significant differences (P > 0.05) were observed in egg production, egg weight, ADFI, and FCR of hens in 60, 300, 600, and 3,000 mg/kg BAs groups. Dietary 60 mg/kg BAs supplementation resulted in a significant increase (P < 0.05) in egg mass. Meanwhile, no significant differences were observed in egg quality, including eggshell strength, eggshell thickness, albumen height, and Haugh unit among any treatment groups (P > 0.05). Dramatically, dietary 3,000 mg/kg BAs supplement decreased yolk color (P < 0.05). There was no significant difference in the blood parameters such as WBC, RBC, HGB, HCT, and PLT among any treatments. However, in 3,000 mg/kg BAs group, ovary coefficient was lower than the control (P < 0.05), and serum urea and creatinine were higher than the control (P < 0.05). Also, kidney and oviduct injury appeared in 3,000 mg/kg BAs group. These results indicated that a porcine BAs concentration of 3,000 mg/kg may cause harmful effects while 600 mg/kg was non-deleterious to laying hens after a daily administration for 56 days, namely that dietary supplement of up to 10 times the recommended dose of BAs was safely tolerated by laying hens.

• National Natural Science Foundation of China
• China Agricultural Research System

• bilirubin
• cholestasis
• endocytosis
• hepatocellular transporters
• oxidative stress
• signaling pathways

Bile acids (BA) as important signaling molecules are considered crucial in development of cholestatic liver injury, but there is limited understanding on the involved cell types and signaling pathways. The aim of this study was to evaluate the inflammatory and fibrotic potential of key BA and the role of distinct liver cell subsets focusing on the NLRP3 inflammasome. C57BL/6 wild-type (WT) and Nlrp3^−/− mice were fed with a diet supplemented with cholic (CA), deoxycholic (DCA) or lithocholic acid (LCA) for 7 days. Additionally, primary hepatocytes, Kupffer cells (KC) and hepatic stellate cells (HSC) from WT and Nlrp3^−/− mice were stimulated with aforementioned BA ex vivo. LCA feeding led to strong liver damage and activation of NLRP3 inflammasome. Ex vivo KC were the most affected cells by LCA, resulting in a pro-inflammatory phenotype. Liver damage and primary KC activation was both ameliorated in Nlrp3-deficient mice or cells. DCA feeding induced fibrotic alterations. Primary HSC upregulated the NLRP3 inflammasome and early fibrotic markers when stimulated with DCA, but not LCA. Pro-fibrogenic signals in liver and primary HSC were attenuated in Nlrp3^−/− mice or cells. The data shows that distinct BA induce NLRP3 inflammasome activation in HSC or KC, promoting fibrosis or inflammation.

• Kupffer cells
• cholestasis
• cholic acid
• deoxycholic acid
• hepatic stellate cells
• inflammagens
• lithocholic acid
• sterile inflammation

• Animals
• Bile Acids and Salts/chemistry
• Bile Acids and Salts/metabolism
• Bile Acids and Salts/pharmacology
• Cholestasis/metabolism
• Cholestasis/pathology
• Liver/metabolism
• Muscle, Skeletal/metabolism
• Oxidation-Reduction
• Oxidative Stress/drug effects
• Reactive Oxygen Species/chemistry
• Reactive Oxygen Species/metabolism
• Receptors, Cytoplasmic and Nuclear/metabolism

• machine learning
• cholestasis
• ascites
• variceal hemorrhage
• encephalopathy

Several studies have indicated that cholestatic liver damage involves mitochondria dysfunction. However, the precise mechanism by which hydrophobic bile salts cause mitochondrial dysfunction is not clear. In this study, we intended to determine the pathogenesis of cholestatic liver injury associated with peroxisome proliferator‐activated receptor‐γ co‐activator 1α (PGC‐1α). A mouse model of cholestatic liver disease was generated by surgical ligation of the bile duct (BDL), and a mouse model of fibrosis was developed through serial administration of thioacetamide. After obtaining liver specimens on scheduled days, we compared the expression of the antioxidant enzymes (superoxide dismutase 2 [SOD2], catalase, and glutathione peroxidase‐1[GPx‐1]) and PGC‐1α in livers from mice with fibrosis and cholestasis using western blotting, immunohistochemistry, and immunofluorescence. We found that cholestatic livers exhibit lower expression of antioxidant enzymes, such as SOD2, catalase, and PGC‐1α. In contrast, fibrotic livers exhibit higher expression of antioxidant enzymes and PGC‐1α. In addition, cholestatic livers exhibited significantly lower expression of pro‐apoptotic markers (Bax) as compared to fibrotic livers. It is well known that overexpression of PGC‐1α increases mitochondrial antioxidant enzyme expression, and vice versa. Thus, we concluded that obstructive cholestasis decreases expression of PGC‐1α, which may lead to decreased expression of mitochondrial antioxidant enzymes, thereby rendering mice with cholestatic livers vulnerable to ROS‐induced cell death.

• antioxidant enzymes
• cholestatic liver disease
• liver fibrosis
• mitochondria
• peroxisome proliferator-activated receptor-γ co-activator 1α

• Bax
• Bcl-2
• Cholestasis
• NeuroAid
• Pgc-1α
• Tfam

• Animals
• Apoptosis/drug effects
• Apoptosis/physiology
• Cholestasis/drug therapy
• Cholestasis/genetics
• Cholestasis/metabolism
• Corpus Striatum/drug effects
• Corpus Striatum/metabolism
• Drugs, Chinese Herbal/pharmacology
• Drugs, Chinese Herbal/therapeutic use
• Gene Expression
• Male
• Organelle Biogenesis
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/biosynthesis
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics
• Proto-Oncogene Proteins c-bcl-2/biosynthesis
• Proto-Oncogene Proteins c-bcl-2/genetics
• Rats
• Rats, Wistar
• Transcription Factors/biosynthesis
• Transcription Factors/genetics
• Treatment Outcome
• bcl-2-Associated X Protein/biosynthesis
• bcl-2-Associated X Protein/genetics

• TBARS
• cortisol
• selenium
• surgical stress
• vitamin E

• Cholestasis
• PBC
• PSC
• liver fibrosis

• Bile Ducts/cytology
• Bile Ducts/immunology
• Bile Ducts/pathology
• Cholangitis/complications
• Cholangitis/immunology
• Cholangitis/pathology
• Cytokines/immunology
• Epithelial Cells/immunology
• Epithelial Cells/pathology
• Fibrosis
• Humans
• Liver/immunology
• Liver/pathology
• Liver Cirrhosis, Biliary/immunology
• Liver Cirrhosis, Biliary/pathology
• Stromal Cells/pathology

• Balanites aegyptiaca
• Hepatotoxicity
• Melatonin
• Methotrexate
• Ursodeoxycholic acid

• Bile duct ligation
• Kidney
• Liver damage
• N-acetyl-l-cysteine
• Oxidative stress

• UH2 TR000503 NCATS NIH HHS
• F32 DK098905 NIDDK NIH HHS
• K99 DK095984 NIDDK NIH HHS
• R00 DK095984 NIDDK NIH HHS
• R21 EB020192 NIBIB NIH HHS

• Bile acid hepatotoxicity
• Cholestasis
• Innate immunity
• Lithocholic acid
• Neutrophils

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-associated liver disease of unknown etiology. The aim of this study was to investigate the change in maternal and fetal adrenal function in clinical and experimental ICP.

The maternal and fetal serum levels of cortisol and dehydroepiandrosterone sulfate (DHEAS) were determined in 14 women with ICP and in pregnant rats with estrogen-induced intrahepatic cholestasis.

In women with ICP, the fetal serum cortisol and DHEAS levels were significantly higher than those in women with normal pregnancy, after correcting the impact of gestational age at delivery. The relationship between fetal cortisol and maternal cholic acid levels was bidirectional; the fetal cortisol tended to increase in mild ICP, while it decreased in severe ICP. In pregnant rats with estrogen-induced cholestasis, the fetal cortisol level was significantly lower in the group with oxytocin injection, compared with the group without oxytocin injection (191.92±18.86 vs. 272.71±31.83 ng/ml, P<0.05). In contrast, the fetal cortisol concentration was increased after oxytocin injection in normal control rats.

The data indicate that fetal stress-responsive system is stimulated in mild ICP, but it is suppressed in severe ICP, which might contribute to the occurrence of unpredictable sudden fetal death. Further studies are warranted to explore the role of impaired fetal adrenal function in the pathogenesis of ICP and the clinical implications.

• Adult
• Aged
• Animals
• Cell Death/drug effects
• Cells, Cultured
• Cholestasis/drug therapy
• Cholestasis/metabolism
• Cholestasis/pathology
• Cholesterol 7-alpha-Hydroxylase/metabolism
• Cytoprotection/drug effects
• Disease Models, Animal
• Female
• Glycochenodeoxycholic Acid/toxicity
• Heme Oxygenase-1/metabolism
• Hepatocytes/cytology
• Hepatocytes/drug effects
• Hepatocytes/metabolism
• Humans
• In Vitro Techniques
• Male
• Membrane Potential, Mitochondrial/drug effects
• Middle Aged
• Nitric Oxide/metabolism
• Nitric Oxide Donors/pharmacology
• Organic Anion Transporters, Sodium-Dependent/genetics
• Organic Anion Transporters, Sodium-Dependent/metabolism
• Oxidative Stress/drug effects
• Protein Processing, Post-Translational/drug effects
• Rats
• Symporters/genetics
• Symporters/metabolism
• Transcription, Genetic/drug effects
• alpha-Tocopherol/pharmacology

• Animals
• Antioxidants/metabolism
• Apoptosis/drug effects
• Base Sequence
• Bile Ducts/surgery
• Cholestasis/complications
• DNA, Mitochondrial/genetics
• Dexamethasone/administration & dosage
• Dexamethasone/pharmacology
• Gene Dosage/genetics
• Glucocorticoids/administration & dosage
• Glucocorticoids/pharmacology
• Ligation
• Liver/drug effects
• Liver/injuries
• Liver/metabolism
• Liver/pathology
• Male
• Mitochondria/drug effects
• Mitochondria/genetics
• Mitochondria/metabolism
• Mitochondria/pathology
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• RNA-Binding Proteins/metabolism
• Rats
• Rats, Sprague-Dawley
• Signal Transduction/drug effects
• Time Factors
• Transcription Factors/metabolism
• Up-Regulation/drug effects

Several studies have characterized the cellular and molecular mechanisms of hepatocyte injury caused by the retention of hydrophobic bile acids (BAs) in cholestatic diseases. BAs may disrupt cell membranes through their detergent action on lipid components and can promote the generation of reactive oxygen species that, in turn, oxidatively modify lipids, proteins, and nucleic acids, and eventually cause hepatocyte necrosis and apoptosis. Several pathways are involved in triggering hepatocyte apoptosis. Toxic BAs can activate hepatocyte death receptors directly and induce oxidative damage, thereby causing mitochondrial dysfunction, and induce endoplasmic reticulum stress. When these compounds are taken up and accumulate inside biliary cells, they can also cause apoptosis. Regarding extrahepatic tissues, the accumulation of BAs in the systemic circulation may contribute to endothelial injury in the kidney and lungs. In gastrointestinal cells, BAs may behave as cancer promoters through an indirect mechanism involving oxidative stress and DNA damage, as well as acting as selection agents for apoptosis-resistant cells. The accumulation of BAs may have also deleterious effects on placental and fetal cells. However, other BAs, such as ursodeoxycholic acid, have been shown to modulate BA-induced injury in hepatocytes. The major beneficial effects of treatment with ursodeoxycholic acid are protection against cytotoxicity due to more toxic BAs; the stimulation of hepatobiliary secretion; antioxidant activity, due in part to an enhancement in glutathione levels; and the inhibition of liver cell apoptosis. Other natural BAs or their derivatives, such as cholyl-N-methylglycine or cholylsarcosine, have also aroused pharmacological interest owing to their protective properties.

• Apoptosis
• Cholestasis
• Liver
• Necrosis
• Oxidative stress
• Ursodeoxycholic acid

The family of bile acids includes a group of molecular species of acidic steroids with very peculiar physical-chemical and biological characteristics. They are synthesized by the liver from cholesterol through several complementary pathways that are controlled by mechanisms involving fine-tuning by the levels of certain bile acid species. Although their best-known role is their participation in the digestion and absorption of fat, they also play an important role in several other physiological processes. Thus, genetic abnormalities accounting for alterations in their synthesis, biotransformation and/or transport may result in severe alterations, even leading to lethal situations for which the sole therapeutic option may be liver transplantation. Moreover, the increased levels of bile acids reached during cholestatic liver diseases are known to induce oxidative stress and apoptosis, resulting in damage to the liver parenchyma and, eventually, extrahepatic tissues. When this occurs during pregnancy, the outcome of gestation may be challenged. In contrast, the physical-chemical and biological properties of these compounds have been used as the bases for the development of drugs and as pharmaceutical tools for the delivery of active agents.

• Cholestasis
• Cholesterol
• Liver
• Metabolism
• Transport

Vesicle-based trafficking of hepatocellular transporters involves delivery of the newly-synthesized carriers from the rough endoplasmic reticulum to either the plasma membrane domain or to an endosomal, submembrane compartment, followed by exocytic targeting to the plasma membrane. Once delivered to the plasma membrane, the transporters usually undergo recycling between the plasma membrane and the endosomal compartment, which usually serves as a reservoir of pre-existing transporters available on demand. The balance between exocytic targeting and endocytic internalization from/to this recycling compartment is therefore a chief determinant of the overall capability of the liver epithelium to secrete bile and to detoxify endo and xenobiotics. Hence, it is a highly regulated process. Impaired regulation of this balance may lead to abnormal localization of these transporters, which results in bile secretory failure due to endocytic internalization of key transporters involved in bile formation. This occurs in several experimental models of hepatocellular cholestasis, and in most human cholestatic liver diseases. This review describes the molecular bases involved in the biology of the dynamic localization of hepatocellular transporters and its regulation, with a focus on the involvement of signaling pathways in this process. Their alterations in different experimental models of cholestasis and in human cholestatic liver disease are reviewed. In addition, the causes explaining the pathological condition (e.g. disorganization of actin or actin-transporter linkers) and the mediators involved (e.g. activation of cholestatic signaling transduction pathways) are also discussed. Finally, several experimental therapeutic approaches based upon the administration of compounds known to stimulate exocytic insertion of canalicular transporters (e.g. cAMP, tauroursodeoxycholate) are described.

• Hepatocellular transporters
• Cholestasis
• cAMP
• Bile salts
• Vesicular trafficking
• Endocytosis
• Signaling pathways

• cholestasis
• liver fibrogenesis
• lipid peroxidation
• oxldl
• oxidative stress

• Animals
• Antioxidants
• Cholestasis/metabolism
• Cholestasis/pathology
• Disease Models, Animal
• Jaundice, Obstructive/metabolism
• Jaundice, Obstructive/pathology
• Lipid Peroxidation/physiology
• Lipoproteins, LDL/metabolism
• Liver Cirrhosis/metabolism
• Liver Cirrhosis/pathology
• Male
• Malondialdehyde/analysis
• Oxidative Stress/physiology
• Random Allocation
• Rats
• Superoxide Dismutase/analysis
• Time Factors