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39 Cards in this Set
- Front
- Back
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Where are nuclear receptors found?
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Mostly in nucleus
Some in the cytoplasm |
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Which molec signal directly to nuclear receptors?
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Small lipophillic molec:
Steroid H Cholesterol metabolites Biles acids Thyroid H Vit A metabolites Vit D3 FA and metabolites Xenobiotics Glucose |
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Which molec signal through membrane receptors?
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Peptide H
Peptide growth factors Small hydrophilic molec (dopamine) |
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At wha level to nuclear receptors exert their physiological activity?
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Regulation of Transcription receptor specific subset of genes in the human genome
->leads to changes in the types/concentrations of ptns present in target cells, .: altering cell fct |
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What were the 1st NR identified for?
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Classical endocrine hormones:
-Steroid H: E, P, androgens, glucocorticoids, mineralocorticoids -Vit D and thyroid H |
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What were receptor-ligand interactions characterized by?
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1) Lipophilicity of the ligand
2) High ligand-receptor specificit 3) High ligand-receptor affinity (low nM) ->H present at low concentration, .: receptor must respond to low concentraion |
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How many genes in the human genome encode nuclear receptors?
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48
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What are orphan H receptors?
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Genes encoding proteins that were novel members of specific classes of H receptors
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What's special about orhpan receptors?
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1) H for classical receptors carry signals that contol many fundamental uman physiological processes (sexual dev'l, reproduction, mineral homeostasis)
2)NR ligands are good candidates for drug dev'l: french abortion pill RU486, block action of P receptor |
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What is the binding to and activation of PXR screen used to assess?
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The capacity of small molec drug candidates to activate their own metabolism and the metabolism of other drugs (drug-drug interactions)
->candidate drugs that are potent activators of PXRs are eliminated from further drug development |
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What do PPARs do?
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Control of lipid metabolism and adipogenesis
(PPARs are toxic) |
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What are the 3 PPAR receptors?
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alpha, beta and gamma
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Where is PPAR-alpha most highly expressed?
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In tissues that display high rates of FA metabolism
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What happens to lgand-activated PPAR-a receptors?
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Stimulate expression of many genes controlling FA metabolism
-> some FA can control their own metabolism through PPARa by inducing the expression of genes encoding metabolic enzymes required for FA catabolism |
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Whre is PPAR-y most expressed?
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Adipose tissue, intestine and spleen
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hat is teh first high affinity ligand for PPAR-y?
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Thioazolidinedione (TZD)
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Why were TZD's first developed?
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Antidiabetic drugs (to type II: insulin independent/resistant)
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What is PPAR-y fct essential to?
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Normal adipogenesis
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How does stimulations of PPAR-y by TZD combat diabetes?
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->lower lvls of circulating FA
-> less fat for fuel ->higherdependence of glucose for fuel |
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What effect does TZD have on muscles?
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Enhances capacity of muscles to burn glucose and repress their capacity to burn fat
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What effect does TZD have on obese ppl with insulin resistance?
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Increases insulin sensitivity, cause slight weight gain (cause not burning fat)
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What does FXR do?
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Control bile metabolism
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What are the two ways that cholesterol meabolism is regulated?
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1) Feed forward mechanism: oxysterols activated production of CYP7A, which is responsible for their conversion to bile acids
2)Feed-back mechanism: elevated levels of bile acids inhibit further bile acid synthesis |
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Where is FXR most highly expressed?
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In tissues where bile acids function: the liver and intestines
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What activates FXR?
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Primary bile acid Chenodeoxycholic acid
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Where are bile acids produced, secreted and transported to?
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Produced in liver
Secreted by bile ducts Transported to the small intestines |
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Why are bile acids impotant?
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-Solubilized excretable forms of cholesterol
-Facilitate absorption of fats and fat-soluble vitamins in the intestine |
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What is the evidence that FXR is a bile receptor?
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1) Bile acid-bound FXR repressed expression of CYP7A which encodes the rate limiting enzyme in cholesterol metabolism to bile acids (provides fdbk mech)
2) Elevateed bile acid lvls induce expression of intestinal bile acid binding protein (IBABP) (Bile acid bound FXR can activate transcription of IBABP gene in intestine) |
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What are DNA microarrays?
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Monitor gene expression
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What has an effect of vit D penetration?
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Latitude (more North, less ozone, more penetration)
Skin color |
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Who has higher levels of crculating vit D metabolite, 25-hydroxyvitamin D3, caucasian or african american?
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Caucasian
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What is the proper amount of vitamin D? What is the limit of sufficiency?
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Proper: 50nM
Limit of sufficiency: ~80 nM |
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What happens when vit D=80nM?
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PTH levels bottom out
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What happens if vit D lvls > 80nM?
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Don't get any more uptake of Ca2+
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What happens at ~ 100nM of vit D?
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Slightly reduced risk of cancer
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Which diseases have north-south gradients?
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1) Certain types of cancer: colon, prostate
2) Autoimmune diseases: multiplke sclerosis, Crohn's disease (highest in Canada) 3) Infectious diseases |
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Where is the highest level of penetration in North America?
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Midwest (a lot of sunlight and also at higher elevation)
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What do macrophages do for vit D?
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When senses infection, increases production of Cyp27B1, which encodes hydroxylase
Hydroxylase converts 25,D precursor to active form of vit D: 1,25-D |
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What happens when cells are treated with 1,25-dihydroxyvitamin D3?
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Induces Secretion of antibacterial activity in the form of anitimicrobial proteins
-> Vit D can help kill bacteria -> Level of 25-D in serum affects the immune response vs bacterial infection |
