No Abstract Available.
Receptors, Cytoplasmic and Nuclear* ; Receptors, Steroid*

No Abstract Available.
Receptors, Cytoplasmic and Nuclear*

The pyruvate dehydrogenase complex (PDC) activity is crucial to maintains blood glucose and ATP levels, which largely depends on the phosphorylation status by pyruvate dehydrogenase kinase (PDK) isoenzymes. Although it has been reported that PDC is phosphorylated and inactivated by PDK2 and PDK4 in metabolically active tissues including liver, skeletal muscle, heart, and kidney during starvation and diabetes, the precise mechanisms by which expression of PDK2 and PDK4 are transcriptionally regulated still remains unclear. Insulin represses the expression of PDK2 and PDK4 via phosphorylation of FOXO through PI3K/Akt signaling pathway. Several nuclear hormone receptors activated due to fasting or increased fat supply, including peroxisome proliferator-activated receptors, glucocorticoid receptors, estrogen-related receptors, and thyroid hormone receptors, also participate in the up-regulation of PDK2 and PDK4; however, the endogenous ligands that bind those nuclear receptors have not been identified. It has been recently suggested that growth hormone, adiponectin, epinephrine, and rosiglitazone also control the expression of PDK4 in tissue-specific manners. In this review, we discuss several factors involved in the expressional regulation of PDK2 and PDK4, and introduce current studies aimed at providing a better understanding of the molecular mechanisms that underlie the development of metabolic diseases such as diabetes.
Adenosine Triphosphate ; Adiponectin ; Blood Glucose ; Epinephrine ; Fasting ; Growth Hormone ; Heart ; Insulin ; Insulin Resistance ; Isoenzymes ; Kidney ; Ligands ; Liver ; Metabolic Diseases ; Muscle, Skeletal ; Oxidoreductases ; Peroxisome Proliferator-Activated Receptors ; Phosphorylation ; Phosphotransferases ; Protein-Serine-Threonine Kinases ; Pyruvate Dehydrogenase Complex ; Pyruvic Acid ; Receptors, Cytoplasmic and Nuclear ; Receptors, Glucocorticoid ; Receptors, Thyroid Hormone ; Starvation ; Thiazolidinediones ; Up-Regulation

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

Estrogen - the female sexual hormone playing the most important role - plays a physiologically significant role, not only regulating in cell signals with second messenger but also being active in regulating transcription. Estrogen receptor (ER) which is a protein accepting estrogen not only play the role of a transcription factor combining with other genes to regulate their activity like other nuclear receptors but also performs external activities, combining with DNA, etc. G-protein coupled ER (GPER) that has been recently discovered exists as 7-membrane and has non-genomic (rapid) signaling. These functions, however, are not extensively addressed. This paper discusses the roles of GPER and its physiological mechanism.
DNA ; Estradiol ; Estrogens* ; Female ; Genomics ; GTP-Binding Proteins* ; Humans ; Receptors, Cytoplasmic and Nuclear ; Second Messenger Systems ; Transcription Factors ; Women's Health*

The nuclear receptors, steroid and xenobiotic receptor (SXR) and constitutive androstane receptor (CAR) play important functions in mediating lipid and drug metabolism in the liver. The present study demonstrates modulatory actions of estrogen in transactivations of SXR-mediated liver X receptor response element (LXRE) and CAR-mediated phenobarbital response element (PBRU). When human estrogen receptor (hERalpha) and SXR were exogenously expressed, treatment with either rifampicin or corticosterone promoted significantly the SXR-mediated transactivation of LXRE reporter gene in HepG2. However, combined treatment with estrogen plus either rifampicin or corticosterone resulted in less than 50% of the mean values of the transactivation by rifampicin or corticosterone alone. Thus, it is suggested that estrogen may repress the SXR-mediated transactivation of LXRE via functional cross-talk between ER and SXR. The CAR-mediated transactivation of PBRU was stimulated by hERalpha in the absence of estrogen. However, the potentiation by CAR agonist, TCPOBOP, was significantly repressed by moxestrol in the presence of ER. Thus, ER may play both stimulatory and inhibitory roles in modulating CAR-mediated transactivation of PBRU depending on the presence of their ligands. In summary, this study demonstrates that estrogen modulates transcriptional activity of SXR and CAR in mediating transactivation of LXRE and PBRU, respectively, of the nuclear receptor target genes through functional cross-talk between ER and the corresponding nuclear receptors.
Corticosterone/pharmacology ; Estrogens/*metabolism ; Ethinyl Estradiol/analogs & derivatives/pharmacology ; Hep G2 Cells ; Humans ; Liver/*metabolism ; Orphan Nuclear Receptors/metabolism ; Phenobarbital/metabolism ; Pyridines/pharmacology ; Receptor Cross-Talk ; Receptors, Cytoplasmic and Nuclear/agonists/*metabolism ; Receptors, Steroid/*metabolism ; Response Elements ; Rifampin/pharmacology ; Transcriptional Activation/*drug effects/physiology

Humans ; Liver Cirrhosis, Biliary ; Receptors, Cytoplasmic and Nuclear

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

OBJECTIVETo investigate the expressions of small heterodimer partner (SHP) and target gene cholesterol-7-hydroxylase (CYP7A1) in livers of rats with intrahepatic cholestasis of pregnancy (ICP), and to study the mechanism of ICP.

METHODSThirty SD rats (pregnant for 15 days) were equally and randomly divided into two groups: an estradiol benzoate (EB) group and a normal saline (NS) group. Two ml blood was drawn from each rat before and on the 5th day after medicine administration to measure the levels of ALT, AST, ALP, TBA, TBIL, and DBIL. After delivery, the histopathological changes of the mother rat livers were studied. The mRNA and protein expressions of SHP and CYP7A1 in the livers were determined by RT-PCR and Western blot.

RESULTS(1) In the EB group, the serum levels of ALT, AST, ALP, TBA, TBil, and DBil after EB administration increased significantly (P less than 0.01), but there were no significant changes in the NS group (P more than 0.05); (2) Intrahepatic cholestasis appeared in the EB group, but not in the NS group; (3) The mRNA expressions of SHP and CYP7A1 were significantly higher in the EB group than in the NS group [(SHPmRNA: NS 0.365+/-0.0317 vs EB 0.4865+/-0.0237, P less than 0.01), (CYP7A1 mRNA: NS 0.3570+/-0.0175 vs EB 0.4802+/-0.0217, P less than 0.01)]; (4) The protein expressions of SHP and CYP7A1 were also higher in the EB group than that in the NS group [(SHP: NS 0.3762+/-0.0284 vs EB 0.5033+/-0.0274, P less than 0.01), (CYP7A1: NS 0.3570+/-0.0175 vs EB 0.4802+/-0.0217, P less than 0.01)].

CONCLUSIONEstrogen induces ICP in rats. The mRNA and protein expressions of SHP and CYP7A1 in livers of the ICP rats were increased, which causes more bile acids to be synthesized. This may be one of the mechanisms of ICP.

Animals ; Cholestasis, Intrahepatic ; chemically induced ; metabolism ; Cholesterol 7-alpha-Hydroxylase ; metabolism ; Estradiol ; analogs & derivatives ; pharmacology ; Female ; Liver ; metabolism ; Pregnancy ; Pregnancy Complications ; chemically induced ; metabolism ; Rats ; Receptors, Cytoplasmic and Nuclear ; metabolism

PURPOSE: Diabetes profoundly and negatively impacts all domains of female sexual function, however, the underlying pathophysiological mechanisms remain unknown. To date, limited studies have been published on the effects of type 1 & type 2 diabetes on female genital sexual arousal and how this may impact overall sexual function. The aim of this review is to discuss the effects of diabetes on female sexual function and insights from laboratory studies on the underlying pathophysiology. MATERIALS AND METHODS: Using PubMed, we reviewed and evaluated the literature published between 1970 and 2009 and data from our laboratories and others investigating the effects of type 1 and type 2 diabetes on genital sexual arousal responses. RESULTS: Women with diabetes experience diminished genital arousal, reduced vaginal lubrication, vaginal atrophy, dyspareunia, and increased vaginal infections. Also, a number of studies using type 1 and type 2 diabetic animal models have reported reduced plasma estradiol levels and marked physiological, biochemical and histological changes in genital tissues. In animal studies, diabetes alters genital tissue structure and attenuates expression of the estrogen, progesterone and androgen receptors and alters vaginal and clitoral hemodynamics. Importantly, treatment of diabetic animals with estradiol in the face of persistent hyperglycemia can restore vaginal structure and sex steroid receptor expression. CONCLUSIONS: Type 1 & type 2 diabetic complications produce significant structural and functional disruptions in genital organs and attenuate genital hemodynamics. In the type 2 animal model, estradiol treatment ameliorates diabetic-induced pathophysiological alterations in genital tissues, such as the vagina. This suggests that estrogen supplementation may be beneficial in restoring diabetes-induced genital pathology.
Animals ; Arousal ; Atrophy ; Clitoris ; Diabetes Complications ; Diabetes Mellitus ; Dyspareunia ; Estradiol ; Estrogens ; Female ; Genitalia ; Hemodynamics ; Humans ; Hyperglycemia ; Lubrication ; Models, Animal ; Plasma ; Progesterone ; Receptors, Androgen ; Receptors, Steroid ; Testosterone ; Vagina