Role of nuclear receptor in the development and progression of primary biliary cholangitis / 临床肝胆病杂志

Primary biliary cholangitis (PBC) is an chronic progressive intrahepatic cholestasis autoimmune liver disease with unknown causes, and at present, the etiology and pathogenesis of PBC remain unclear. Nuclear receptor is a ligand-dependent transcription factor superfamily that regulates cell growth and differentiation by establishing a relationship between signal molecules and transcriptional responses. The human nuclear receptor family consists of 48 members, including peroxisome proliferator-activated receptors, pregnane X receptor, constitutive androstane receptor, liver X receptors, farnesoid X receptor, vitamin D receptor, and glucocorticoid receptor, which have attracted wide attention. These nuclear receptors regulate the key enzymes and transporter genes of bile acid metabolism at the transcriptional level and thus regulate the level of bile acid in the body and participate in inflammatory response. Bile acid metabolism disorder and persistent inflammation may be the key factors for the development and progression of PBC. This article reviews the research advances in nuclear receptors in the development and progression of PBC, in order to provide a theoretical basis for exploring the pathogenesis of PBC and new therapeutic targets.

Understanding Bile Acid Signaling in Diabetes: From Pathophysiology to Therapeutic Targets

Diabetes and obesity have reached an epidemic status worldwide. Diabetes increases the risk for cardiovascular disease and non-alcoholic fatty liver disease. Primary bile acids are synthesized in hepatocytes and are transformed to secondary bile acids in the intestine by gut bacteria. Bile acids are nutrient sensors and metabolic integrators that regulate lipid, glucose, and energy homeostasis by activating nuclear farnesoid X receptor and membrane Takeda G protein-coupled receptor 5. Bile acids control gut bacteria overgrowth, species population, and protect the integrity of the intestinal barrier. Gut bacteria, in turn, control circulating bile acid composition and pool size. Dysregulation of bile acid homeostasis and dysbiosis causes diabetes and obesity. Targeting bile acid signaling and the gut microbiome have therapeutic potential for treating diabetes, obesity, and non-alcoholic fatty liver disease.

Nuclear Receptors Resolve Endoplasmic Reticulum Stress to Improve Hepatic Insulin Resistance

Chronic endoplasmic reticulum (ER) stress culminating in proteotoxicity contributes to the development of insulin resistance and progression to type 2 diabetes mellitus. Pharmacologic interventions targeting several different nuclear receptors have emerged as potential treatments for insulin resistance. The mechanistic basis for these antidiabetic effects has primarily been attributed to multiple metabolic and inflammatory functions. Here we review recent advances in our understanding of the association of ER stress with insulin resistance and the role of nuclear receptors in promoting ER stress resolution and improving insulin resistance in the liver.

Bile Acid Nuclear Receptor Farnesoid X Receptor: Therapeutic Target for Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is one of the causes of fatty liver, occurring when fat is accumulated in the liver without alcohol consumption. NAFLD is the most common liver disorder in advanced countries. NAFLD is a spectrum of pathology involving hepatic steatosis with/without inflammation and nonalcoholic steatohepatitis with accumulation of hepatocyte damage and hepatic fibrosis. Recent studies have revealed that NAFLD results in the progression of cryptogenic cirrhosis that leads to hepatocarcinoma and cardiovascular diseases such as heart failure. The main causes of NAFLD have not been revealed yet, metabolic syndromes including obesity and insulin resistance are widely accepted for the critical risk factors for the pathogenesis of NAFLD. Nuclear receptors (NRs) are transcriptional factors that sense environmental or hormonal signals and regulate expression of genes, involved in cellular growth, development, and metabolism. Several NRs have been reported to regulate genes involved in energy and xenobiotic metabolism and inflammation. Among various NRs, farnesoid X receptor (FXR) is abundantly expressed in the liver and a key regulator to control various metabolic processes in the liver. Recent studies have shown that NAFLD is associated with inappropriate function of FXR. The impact of FXR transcriptional activity in NAFLD is likely to be potential therapeutic strategy, but still requires to elucidate underlying potent therapeutic mechanisms of FXR for the treatment of NAFLD. This article will focus the physiological roles of FXR and establish the correlation between FXR transcriptional activity and the pathogenesis of NAFLD.

Targeting the Peroxisome Proliferator-Activated Receptor-gamma to Counter the Inflammatory Milieu in Obesity

Adipose tissue, which was once viewed as a simple organ for storage of triglycerides, is now considered an important endocrine organ. Abnormal adipose tissue mass is associated with defects in endocrine and metabolic functions which are the underlying causes of the metabolic syndrome. Many adipokines, hormones secreted by adipose tissue, regulate cells from the immune system. Interestingly, most of these adipokines are proinflammatory mediators, which increase dramatically in the obese state and are believed to be involved in the pathogenesis of insulin resistance. Drugs that target peroxisome proliferator-activated receptor-gamma have been shown to possess anti-inflammatory effects in animal models of diabetes. These findings, and the link between inflammation and the metabolic syndrome, will be reviewed here.

Transcriptional Regulation of Pyruvate Dehydrogenase Kinase

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.

Expression and clinical significance of constitutive androstane receptor in placental syntrophoblast of intrahepatic cholestasis of pregnancy / 中华妇产科杂志

Objective To explore the expression and clinical significance of constitutive androstane receptor(CAR)in placenta syntrophoblast from patients with intrahepatic cholestasis of pregnancy(ICP).Methods Placenta were collected from women with ICP who delivered from April 2009 to March 2010 in First Affiliated Hospital of Chongqing Medical University.According to the severity of ICP,patients were classified into mild ICP group(n=10)and severe ICP group(n=10).Ten healthy pregnant women who delivered in the same period were chosen as control group.The location of CAR protein in placenta was studied by immunohistochemical streptavidin-biotin complex(SABC)method.CAR mRNA level was determined by reverse transcription(RT)-PCR technique and CAR protein expression level was determined by western blot.Results(1)CAR was located in the placenta syncytiotrophoblastic cells in control group and mild ICP group,showed light tan when stained,and was mainly in the cytoplasm.In severe ICP group,CAR was also located in placenta syncytiotrophoblastic cells but mainly in the nucleolus,showed dark tan when stained.(2)The mRNA expressions of CAR in control group,mild ICP group,severe ICP group were 0.06 ±0.03,0.07 ±0.03 and 0.56±0.03.respectively.CAR in severe ICP group was significantly higher than those in control group and mild ICP group(P＜0.05).The difference of mRNA between control group and mild ICP group wag not statistically significant(P＞0.05).(3)The CAR protein levels in control group,mild ICP group,severe ICP group were 0.74±0.03,0.79±01 03 and 1.02±0.04,respectively.CAR protein expression in the severe ICP group was significantly higher than the other two groups(P＜0.05).And there was no statistical significance between mild group and control group(P＞0.05).Conclusion In ICP women.especially severe ICP patients,the CAR expression in placenta syncytiotrophoblastic cells increased appreciably,which may be involved in the maintenance of placenta barrier function and protection in ICP pathogenesis.

Nuclear receptor regulation of stemness and stem cell differentiation

Stem cells include a diverse number of toti-, pluri-, and multi-potent cells that play important roles in cellular genesis and differentiation, tissue development, and organogenesis. Genetic regulation involving various transcription factors results in the self-renewal and differentiation properties of stem cells. The nuclear receptor (NR) superfamily is composed of 48 ligand-activated transcription factors involved in diverse physiological functions such as metabolism, development, and reproduction. Increasing evidence shows that certain NRs function in regulating stemness or differentiation of embryonic stem (ES) cells and tissue-specific adult stem cells. Here, we review the role of the NR superfamily in various aspects of stem cell biology, including their regulation of stemness, forward- and trans-differentiation events; reprogramming of terminally differentiated cells; and interspecies differences. These studies provide insights into the therapeutic potential of the NR superfamily in stem cell therapy and in treating stem cell-associated diseases (e.g., cancer stem cell).

?_1-antichymotrypsin interaction with Alzheimer’s peptide A?_(1-42) in affecting expression of transcription factors in human neuroblastoma cells / 中华神经科杂志

Objective To study the interaction between ?_1-antichymotrypsin (ACT) and amyloid peptide A?_~1-42 in vitro, and the effects of their complex on expression of transcription factors PPAR? and NF?B in human neuroblastoma (Kelly) cells. Methods A?_~1-42 and ACT were mixed at a 10∶1 molar ratio at room temperature, the complex formed in 2 hours and 24 hours were expressed as A?_~1-42 /ACT (2 hours), A?_~1-42 /ACT (24 hours), respectively. The complexes were studied by using agrose electrophoresis, and their effects on PPAR? and NF?B expressions were assessed by electrophoresis mobility shift assay (EMSA). Results At conditions used, ACT interacted with A?_~1-42 in vitro, the complexes formed and functioned differently according to their interaction period. Compared with unstimulated control cells, A?_~1-42 /ACT (2 hours) strongly increased PPAR? and NF?B expressions by Kelly cells by 158% (P

Effect of peroxisome proliferators-activated receptor ? ligands on cytotrophoblast invasion in first trimester pregnancy / 中华妇产科杂志

Objective To investigate the expression of peroxisome proliferators-activated receptor ? (PPAR?) in trophoblast and relation between PPAR? ligands and trophoblast invasion.Methods We examined the expression of PPAR? by immunohistochemistry,immunocytochemistry and real time quantitative PCR.We next examined,using the cytotrophoblast culture model,the biological role of PPAR? ligands in vitro.Results PPAR? was mainly localized in the nuclei of villous cytotrophoblast and extravillous cytotrophoblast of cell islands and cell columns.In villous tissue and cultured trophoblast from early first trimester,the level of expression of PPAR? mRNA and protein was 36.0?5.1,13.4?3.1 and 1.35?0.08,1.13?0.11;from late first trimester it was 23.3?5.5,6.1?1.3 and 1.17?0.03,0.86 ?0.05,and the expression of PPAR? was obviously decreased (P