Cholestatic liver diseases are characterized by impairments of bile flows and accumulations of biliary constituents such as bile acids and bilirubin. The changes of phase I and II metabolism and the hepatobiliary transport system minimize cholestatic liver injury. These adaptive responses are transcriptionally regulated by several nuclear receptors. Recent studies have revealed that the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) are key nuclear receptors for regulating many of the adaptive responses noted in cholestasis. PXR and CAR coordinately regulate not only bile acid metabolism and transport, but also bilirubin clearance. PXR and CAR ligands may be useful in the future for the treatment of cholestatic liver disease.
Transcription Factors/metabolism/*physiology ; Receptors, Steroid/metabolism/*physiology ; Receptors, Cytoplasmic and Nuclear/metabolism/*physiology ; Humans ; Cholestasis/metabolism/*physiopathology

Over the past decade, there has been increasing attention on the interaction between microbiota and bile acid metabolism. Bile acids are not only involved in the metabolism of nutrients, but are also important in signal transduction for the regulation of host physiological activities. Microbial-regulated bile acid metabolism has been proven to affect many diseases, but there have not been many studies of disease regulation by microbial receptor signaling pathways. This review considers findings of recent research on the core roles of farnesoid X receptor (FXR), G protein-coupled bile acid receptor (TGR5), and vitamin D receptor (VDR) signaling pathways in microbial-host interactions in health and disease. Studying the relationship between these pathways can help us understand the pathogenesis of human diseases, and lead to new solutions for their treatments.
Bile Acids and Salts/metabolism* ; Gastrointestinal Microbiome ; Humans ; Inflammation/metabolism* ; Metabolic Syndrome/metabolism* ; Receptors, Calcitriol/physiology* ; Receptors, Cytoplasmic and Nuclear/physiology* ; Receptors, G-Protein-Coupled/physiology* ; Signal Transduction/physiology*

No abstract available.
Calcium Channels/metabolism* ; Calcium Signaling/physiology* ; Cyclic AMP-Dependent Protein Kinases/metabolism* ; Pancreas/enzymology* ; Periodicity ; Phosphorylation ; Receptors, Cytoplasmic and Nuclear/metabolism*

AIMTo investigate the roles of liver X receptors (LXR) in the lipid composition and gene expression regulation in the murine caput epididymidis. LXR are nuclear receptors for oxysterols, molecules derived from cholesterol metabolism that are present in mammals as two isoforms: LXRalpha, which is more specifically expressed in lipid-metabolising tissues, such as liver, adipose and steroidogenic tissues, and macrophages, whereas LXRbeta is ubiquitous. Their importance in reproductive physiology has been sustained by the fact that male mice in which the function of both LXR has been disrupted have fertility disturbances starting at the age of 5 months, leading to complete sterility by the age of 9 months. These defects are associated with epididymal epithelial degeneration in caput segments one and two, and with a sperm midpiece fragility, leading to the presence of isolated sperm heads and flagella when luminal contents are recovered from the cauda epididymidis.

METHODSThe lipid composition of the caput epididymidis of wild-type and LXR-deficient mice was assessed using oil red O staining on tissue cryosections and lipid extraction followed by high performance liquid chromatography or gas chromatography. Gene expression was checked by quantitative real time polymerase chain reaction.

RESULTSUsing LXR-deficient mice, we showed an alteration of the lipid composition of the caput epididymidis as well as a significantly decreased expression of the genes encoding SREBP1c, SCD1 and SCD2, involved in fatty acid metabolism.

CONCLUSIONAltogether, these results show that LXR are important regulators of epididymal function, and play a critical role in the lipid maturation processes occurring during sperm epididymal maturation.

Animals ; DNA Primers ; DNA-Binding Proteins ; deficiency ; genetics ; physiology ; Epididymis ; cytology ; physiology ; Epithelial Cells ; physiology ; Fatty Acids ; metabolism ; Homeostasis ; Lipids ; physiology ; Liver X Receptors ; Male ; Mice ; Mice, Knockout ; Orphan Nuclear Receptors ; Polymerase Chain Reaction ; Receptors, Cytoplasmic and Nuclear ; deficiency ; genetics ; physiology

Peroxisome proliferation is a cellular response to many chemical compounds affects including natural and modified fatty acids, phthalate and adipate ester plasticizers, leukotriene antagonists, acetylsalicylic acid and certain pathophysiological conditions including dramatic change of cellular morphology and enzymatic activity. Peroxisome proliferation phenomenon is seen primarily in liver and kidney. Hormones and nutritional factor can regulate peroxisome proliferation response. Sustained peroxisome proliferation can lead to hepatocarcinogenesis. The three types of peroxisome proliferator activated receptor, termed PPAR alpha, PPAR beta, and PPAR gamma, expressed in specific tissue, are consisted of a specific a nuclear receptor superfamily. After more than 10 years world wide research, the function of PPAR is clarified, as PPAR gamma, the master of thrifty genes, controls the expression of genes relative to adipogenesis, diabetes mellitus and obesity. The receptor is involved in transcriptional control of numerous cellular processes including cell cycle control, inflammation, immunoregulation and carcinogenesis.
Adipocytes ; cytology ; Animals ; Cell Differentiation ; Energy Metabolism ; genetics ; Humans ; Intracellular Signaling Peptides and Proteins ; Nuclear Receptor Coactivators ; Peroxisome Proliferators ; Receptors, Cytoplasmic and Nuclear ; genetics ; physiology ; Transcription Factors ; genetics ; physiology

Androgens control a broad range of physiological functions. The androgen receptor (AR), a steroid receptor that mediates the diverse biological actions of androgens, is a ligand inducible transcription factor. Abnormalities in the androgen signaling system result in many disturbances ranging from changes in gender determination and sexual development to psychiatric and emotional disorders. Androgen replacement therapy can improve many clinical conditions including hypogonadism and osteoporosis, but is limited by the lack of efficacious and safe therapeutic agents with easy delivery options. Recent progress in the area of gene regulation by steroid receptors and by selective receptor modulators provides an opportunity to examine if selective androgen receptor modulators (SARMs) could address some of the problems associated with current androgen therapy. Since the composition of the transcriptional initiation complex recruited by liganded AR determines the specificity of gene regulation, synthetic ligands aimed at initiating transcription of tissue and promoter specific genes offers hope for developing better androgen therapy. Establishment of assays that predict synthetic ligand activity is critical for SARM development. Advancement in high throughput compound screening and gene fingerprinting technologies, such as microarrays and proteomics, will facilitate and accelerate identification of effective SARMs.
Androgen Antagonists ; pharmacology ; Androgen Receptor Antagonists ; Androgens ; chemistry ; metabolism ; Chlormadinone Acetate ; analogs & derivatives ; pharmacology ; Humans ; Male ; Receptors, Androgen ; physiology ; Receptors, Cytoplasmic and Nuclear ; physiology ; Testosterone Congeners ; pharmacology

Rafts, cholesterol- and sphingolipid-rich membrane microdomains, have been shown to play an important role in immune cell activation. More recently rafts were implicated in the signal transduction by members of the TNF receptor (TNFR) family. In this study, we provide evidences that the raft microdomain has a crucial role in RANK (receptor activator of NF-kappaB) signaling. We found that the majority of the ectopically expressed RANK and substantial portion of endogenous TRAF2 and TRAF6 were detected in the low-density raft fractions. In addition, TRAF6 association with rafts was increased by RANKL stimulation. The disruption of rafts blocked the TRAF6 translocation by RANK ligand and impeded the interaction between RANK and TRAF6. Our observations demonstrate that proper RANK signaling requires the function of raft membrane microdomains.
Carrier Proteins/metabolism ; Glycoproteins/*metabolism ; Human ; Membrane Glycoproteins/metabolism ; Membrane Microdomains/*metabolism ; Protein Transport/physiology ; Proteins/*metabolism ; Receptors, Cytoplasmic and Nuclear/*metabolism

Animals ; DNA-Binding Proteins ; physiology ; Homeostasis ; Humans ; Lipid Metabolism ; Liver ; metabolism ; Liver X Receptors ; NF-kappa B ; physiology ; Nuclear Proteins ; physiology ; Orphan Nuclear Receptors ; Peroxisome Proliferator-Activated Receptors ; physiology ; Receptors, Cytoplasmic and Nuclear ; physiology ; Sterol Regulatory Element Binding Proteins ; physiology ; Transcription Factors ; physiology

Nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are originally characterized as transcription factors regulating many target genes. Recent works have revealed that these nuclear receptors play critical roles in regulating genes that encode drug metabolism enzymes and modulating hepatic energy metabolism, such as down-regulating gluconeogenesis, fatty acid oxidation, and ketogenesis, as well as up-regulating lipogenesis. Studies on PXR and CAR have important implication on drug-drug interaction (DDI) and potential disease treatment targets.
Animals ; Drug Interactions ; Energy Metabolism ; Glucose ; metabolism ; Glucose-6-Phosphate ; metabolism ; Humans ; Inflammation ; metabolism ; Lipid Metabolism ; Liver ; metabolism ; NF-kappa B ; metabolism ; Receptors, Cytoplasmic and Nuclear ; physiology ; Receptors, Steroid ; physiology

Phytochemicals, orally administered substances, are found to undergo presystemic metabolism mainly in the intestine. Although early researches confirmed the role of intestinal bacteria in phytochemical presystemic metabolism, along with the development of molecular biology in investigating intestinal metabolism, a breakthrough has been won in research into metabolizing enzymes and transporters in intestine, which demands more attention and further studies. Recently, Cytochrome P450 3A has been found to be the most effective enzyme in mediating both oxidative (PhaseI) and conjugative (PhaseII) metabolism in the intestine. The present review summarizes the current findings correlated with the effect of intestinal cytochrome P450 3A on phytochemical presystemic metabolism, which provides a good basis for further research on phytochemical pharmacokinetics.
ATP-Binding Cassette, Sub-Family B, Member 1 ; metabolism ; Animals ; Biotransformation ; physiology ; Cytochrome P-450 CYP3A ; physiology ; Drug Interactions ; physiology ; Drugs, Chinese Herbal ; metabolism ; Herb-Drug Interactions ; physiology ; Humans ; Intestines ; metabolism ; Receptors, Cytoplasmic and Nuclear ; metabolism