A5043198039- Adipokines, Inflammation, and Metabolic Diseases
- Adipose Tissue and Metabolism
- Drug Transport and Resistance Mechanisms
- Pharmacogenetics and Drug Metabolism
- Eicosanoids and Hypertension Pharmacology
- Regulation of Appetite and Obesity
- Peroxisome Proliferator-Activated Receptors
- Cholesterol and Lipid Metabolism
- Apelin-related biomedical research
- Bone Metabolism and Diseases
- Gut microbiota and health
- Pediatric Hepatobiliary Diseases and Treatments
- Muscle Physiology and Disorders
- Drug-Induced Hepatotoxicity and Protection
- Cardiovascular Disease and Adiposity
- Pharmacological Effects and Toxicity Studies
- Clostridium difficile and Clostridium perfringens research
- Stress Responses and Cortisol
- Neuroendocrine regulation and behavior
- Galectins and Cancer Biology
- Diet and metabolism studies
- Cytokine Signaling Pathways and Interactions
- Bone and Joint Diseases
- Exercise and Physiological Responses
- Mesenchymal stem cell research
Dalhousie University
2014-2024
Izaak Walton Killam Health Centre
2004-2015
ChemoCentryx (United States)
2013
Michigan State University
2000-2013
Faculty (United Kingdom)
2008
The University of Texas Southwestern Medical Center
2006
University of Alberta
2006
Duke University Hospital
2006
Duke Medical Center
2006
University of North Carolina at Chapel Hill
2006
Obesity is an alarming primary health problem and independent risk factor for type II diabetes, cardiovascular diseases, hypertension. Although the pathologic mechanisms linking obesity with these co-morbidities are most likely multifactorial, increasing evidence indicates that altered secretion of adipose-derived signaling molecules (adipokines; e.g. adiponectin, leptin, tumor necrosis alpha) local inflammatory responses contributing factors. Chemerin (RARRES2 or TIG2) a recently discovered...
This article is a report on symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics held at Biology 07 meeting in Washington, DC. The presentations discussed phenomenology, clinical consequences, underlying mechanisms of cytochrome P450 drug transporter regulation inflammatory infectious stimuli. Although considerable insights into links between mediators altered hepatic clearance pathways have been gained from previous studies with acute stimuli, this...
To address the importance of farnesoid X-receptor (FXR; NR1H4) for normal cholesterol homeostasis, we evaluated major pathways metabolism in the<i>FXR</i>-deficient (−/−) mouse model. Compared with wild-type,<i>FXR</i>(−/−) mice have increased plasma high density lipoprotein (HDL) and a markedly reduced rate HDL ester clearance. Concomitantly, <i>FXR</i>(−/−) exhibit expression hepatic genes involved reverse transport, most notably, that scavenger receptor BI.<i>FXR</i>(−/−) also increased:...
Peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) has been shown to regulate adaptive thermogenesis and glucose metabolism. Here we show that PGC-1alpha regulates triglyceride metabolism through both farnesoid X receptor (FXR)-dependent -independent pathways. increases FXR activity two pathways: (1) it mRNA levels by coactivation of PPARgamma HNF4alpha enhance gene transcription; (2) interacts with the DNA-binding domain transcription target genes. Ectopic...
Obesity, characterized by an excess of adipose tissue, is established risk factor for cardiovascular disease and type 2 diabetes. Different mechanisms linking obesity with these comorbidities have been postulated but remain poorly understood. Adipose tissue secretes a number hormone-like compounds, termed adipokines, that are important the maintenance normal glucose metabolism. Alterations in secretion adipokines believed to contribute undesirable changes metabolism ultimately result...
Sister of P-glycoprotein (SPGP) is the major hepatic bile salt export pump (BSEP). BSEP/SPGP expression varies dramatically among human livers. The potency and hierarchy acids as ligands for farnesyl/bile acid receptor (FXR/BAR) paralleled their ability to induce BSEP in hepatocyte cultures. FXR:RXR heterodimers bound IR1 elements enhanced transcriptional activation mouse promoters. In FXR/BAR nullizygous mice, which have reduced levels, CYP3A11 CYP2B10 were strongly but unexpectedly...
Renal microsomal cytochrome P-450 monooxygenase-dependent metabolism of arachidonic acid generates a series regioisomeric epoxyeicosatrienoic acids that can be further metabolized by soluble epoxide hydrolase to the corresponding dihydroxyeicosatrienoic acids. Evidence exists these metabolites affect renal function and, in particular, blood pressure regulation. To examine this possibility, and were examined mice with targeted disruption gene. Systolic male hydrolase-null was lower compared...
The farnesoid X-activated receptor (FXR; NR1H4), a member of the nuclear hormone superfamily, induces gene expression in response to several bile acids, including chenodeoxycholic acid. Here we used suppression subtractive hybridization identify apolipoprotein C-II (apoC-II) as an FXR target gene. Retroviral HepG2 cells results induction mRNA encoding apoC-II ligands. EMSAs demonstrate that recombinant and RXR bind two elements are contained within important distal enhancer (hepatic control...
The nuclear receptors, farnesoid X receptor (FXR) and pregnane (PXR), are important in maintaining bile acid homeostasis. Deletion of both FXR PXR vivo by cross-breeding B6;129-Fxrtm1Gonz (FXR-null) B6;129-Pxrtm1Glaxo-Wellcome (PXR-null) mice revealed a more severe disruption acid, cholesterol, lipid homeostasis Pxrtm1Glaxo-Wellcome (FXR-PXR double null or FPXR-null) fed 1% cholic (CA) diet. Hepatic expression the constitutive androstane (CAR) its target genes was induced FXR- FPXR-null CA...
Heme metabolism normally involves enzymatic conversion to biliverdin and subsequently bilirubin, catalyzed by heme oxygenase reductase, respectively. We examined the ability of exogenously added hemin, biliverdin, or bilirubin regulate Cyp1a1, an enzyme that may be active in elimination. A substantial dose-dependent increase Cyp1a1 mRNA occurred after treatment Hepa 1c1c7 cells with either three compounds. This was readily apparent 1 hr but required ≥2 hemin. Treatment these compounds also...
Intestinal reclamation of bile salts is mediated in large part by the apical sodium-dependent acid transporter (ASBT). The responsiveness ASBT controversial. Bile feeding mice results decreased expression protein and mRNA. Mouse but not rat promoter activity was repressed Caco-2, IEC-6, cells chenodeoxycholic acid. A potential liver receptor homologue-1 (LRH-1) cis-acting element identified acid-responsive region mouse promoter. mouse, rat, activated LRH-1, this correlated with nuclear...
Cytochrome P450 epoxygenases metabolize arachidonic acid to epoxyeicosatrienoic acids (EETs) which are converted dihydroxyeicosatrienoic (DHETs) by soluble epoxide hydrolase ( Ephx2 , sEH). To examine the functional role of sEH in heart, mice with targeted disruption gene were studied. Hearts from null have undetectable levels mRNA and protein cannot convert EETs DHETs. normal heart anatomy basal contractile function, but higher fatty epoxide:diol ratios plasma cardiomyocyte cell culture...
This study developed an approach to quantify frailty with a index (FI) and investigated whether age-related changes in contractions, calcium transients, ventricular myocyte length were more prominent mice high FI. The FI combined 31 variables that reflect different aspects of health middle-aged (∼12 months) aged (∼30 both sexes. Aged animals had higher than younger (FI = 0.43 ± 0.03 vs 0.08 0.02, p < .001, n 12). Myocyte hypertrophy increased by 30%-50% as the animals. Peak contractions...
The farnesoid X receptor (FXR) is a bile acid-activated transcription factor that regulates the expression of genes critical for acid and lipid homeostasis. This study was undertaken to investigate pathological consequences loss FXR function on risk severity atherosclerosis. For this purpose, FXR-deficient (FXR−/−) mice were crossed with apolipoprotein E-deficient (ApoE−/−) generate FXR−/−ApoE−/− mice. Challenging these high-fat, high-cholesterol (HF/HC) diet resulted in reduced weight gain...
Adipose tissue secretes a variety of bioactive signaling molecules, termed adipokines, which regulate numerous biological functions including appetite, energy balance, glucose homeostasis, and inflammation. Chemerin is novel adipokine that regulates adipocyte differentiation metabolism by binding to activating the G protein-coupled receptor, chemokine like receptor-1 (CMKLR1). In present study, we investigated impact CMKLR1 deficiency on adipose development, inflammation in vivo. Herein...
Maintenance of healthy bone mass requires a well-coordinated balance between the ongoing processes formation and resorption. Bone-forming osteoblasts derive from resident adult stem cells within marrow called stromal (BMSCs). These BMSCs are multipotent also can give rise to adipocytes, which do not contribute directly but may influence remodeling through release bioactive signaling molecules. Chemerin is novel adipocyte-derived molecule that promotes adipocyte differentiation. In this study...
Chemerin is an adipokine with important regulatory roles in adipogenesis. In humans, serum total chemerin (i.e. prochemerin plus chemerin) levels are positively associated body mass index and metabolic syndrome. However, the mechanisms that increase concentration unknown. We hypothesized chronic low-grade inflammation occurs obesity promotes production by adipocytes. Consistent this, TNFα treatment of 3T3-L1 adipocytes increased bioactive cell media as detected using a CMKLR1 cell-based...
Objective— Obesity and hypertension are comorbid in epidemic proportion, yet their biological connection is largely a mystery. The peptide chemerin candidate for connecting fat deposits around the blood vessel (perivascular adipose tissue) to arterial contraction. We presently tested hypothesis that expressed perivascular tissue vasoactive, supporting existence of axis vasculature. Approach Results— Real-time polymerase chain reaction, immunohistochemistry, Western analyses supported...
Chemerin is an adipose-derived signaling protein (adipokine) that regulates adipocyte differentiation and function, immune metabolism, glucose homeostasis through activation of chemokine-like receptor 1 (CMKLR1). A second chemerin receptor, G protein-coupled (GPR1) in mammals, binds with affinity similar to CMKLR1; however, the function GPR1 mammals essentially unknown. Herein, we report expression murine Gpr1 mRNA high brown adipose tissue white (WAT) skeletal muscle. In contrast (Rarres2)...
Chemerin is an adipocyte-secreted protein that regulates adipogenesis and the metabolic function of mature adipocytes via activation chemokine-like receptor 1 (CMKLR1). Herein we report interaction peroxisome proliferator-activated γ (PPARγ) chemerin in context adipogenesis. Knockdown or CMKLR1 expression antibody neutralization secreted arrested adipogenic clonal expansion bone marrow mesenchymal stem cells (BMSCs) by inducing a loss G(2)/M cyclins (cyclin A2/B2) but not G(1)/S cyclin D2....