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PHGY 210
Anne- Marie Lauzon

WEEK  3   Monday,  January  1 7 ,  2011   PHGY  210   Dr.  White     Continued  from  last  lecture   • Orphan  receptors  refer  to  receptors  that,  upon  discovery,  did  not  have  any  known  physiological  ligands     PPARs:  Control  of  Lipid  Metabolism  and  Adipogenesis     • There  are  3  PPAR  receptors,  α,  β,  and  γ.  (in  the  USA  they  are  referred  to  alpha  delta  and  gamma)   • Focus  on  PPAR  α  and  γ  -­‐  best  characterized  and  most  interesting  receptors   • The  name  PPAR  (peroxisomal  proliferator -­‐activated  receptor)  was  derived  from  observation  that  at   high  concentrations,  PPARs  bind  classes  of  toxic  compounds  that  cau sed  proliferation  of  peroxisome   organelles  in  livers  of  rats   o The  same  phenomenon  is  not  observed  in  humans,  but  the  compounds  are  toxic  anyway     PPARα   • Most  highly  expressed  in  tissues   that  display  high  rates  of  fatty   acid  metabolism.   • Subsequent  to  discovery  that  PPAR α  bound  peroxisomal   proliferators,  it  was  discovered  that   PPARα  bound  certain   types  of  fatty  acids  and  their  metabolites .   • More  recently,  it  was  shown  that  ligand-­‐bound  (ie:  activated)  PPARα  receptors  stimulated  expression   of  several  genes  controlling  fatty  acid  metabolism   o Thus,  some  fatty  acids  can  control  their  own  metabolism  through  PPAR α  by  inducing  the  expression  of   genes  encoding  metabolic  enzymes  required  for  fatty  acid  catabolism.     PPARγ   • Most  fascinating  of  all  orphan  receptors   • Most  highly  expressed  in   adipose  tissue,  intestine  and  spleen   • The  First  high  affinity  ligand  for  PPAR γ  was  identified  in  a  large  ligand  screen  at  Glaxo -­‐Wellcome,  and   turned  out  to  be  a  thiazolidinedione  (TZD)   o TZDs  are  fascinating  because  they  were  originally  developed  as   antidiabetic  drugs,  although  their   molecular  targets  were   unknown.   • More  effective  TZDs  were  rapidly  developed,  and  are  widel y  used  in  diabetes  therapy  today     PPARγ  and  Insulin  Resistant  Diabetes   • PPARγ  function  is  essential  for  normal  adipogenesis   • Given  that  stimulation  of  PPARγ  is  adipogenic,  and  that  obesity  is  correlated  with  insulin  resistance  and   diabetes,  how  is  it  that  stimulation  of  PPARγ  by  TZD  combats  diabetes ?   o The  antidiabetic  action  of  TZDs  arises  from  the  fact  that  they   lower  circulating  levels  of  fatty   acids,  leaving  less  fat  in  the  circulation  to  be  used  as  fuel,  and  therefore  a  higher  dependence  of   glucose  as  fuel.   o Effective  in  type  II  diabetes  patients  (ca used  by  isulin  resistance)   • This  is  particularly  true  in  muscle,  and  recent  studies  have  shown  that  TZD  signaling  enhances  the  capacity   of  muscles  to  burn  glucose  and  represses  their  capacity  to  burn  fat.   • As  a  result,  TZDs  are  very  effective  in  obese  people  with  insulin  resistance,  where  they  significantly   increase  insulin  sensitivity,  and  actually  cause  slight  weight  gains.     FXR:  Control  of  Bile  Acid  Metabolism   • The  term  FXR  is  derived  from  early  observations  that   FXR  could  be  activated  by  extremely  high   concentrations  of  farnesyl,  an  intermediate  in  cholesterol  biosynthesis.       1   WEEK  3   o However,  it  was  subsequently  shown  that   farnesyl  does  not  actually  bind  to  FXR,  and  therefore,   that  some  metabolite  was  responsible  for  the  activation  observation  at  extremely  high   concentrations.   • FXR  is  actually  a  receptor  for  Bile  Acids   o Bile  acids  are  breakdown  products  of  cholesterol   o In  bile  acids,  we  have  lost  a  sidechain  of  cholesterol  and  replaced  it  with  a  water -­‐soluble  carboxylic   acid.  These  acids  will  have  hydrophobic  and  hy drophilic  parts  and  can  solubilize  lipid  components   of  the  diets.   • Cholesterol  metabolism  is  controlled  in  two  ways:   o 1)  A  feed-­‐forward  mechanism  whereby   oxysterols  (cholesterol  metabolites)  activate   production  of  CYP7A,  the  enzyme  responsible  for  the  rate  limiting  step  of  their  conversion  to  bile   acids.   o 2)  A  feed-­‐back  mechanism  whereby   elevated  levels  of  bile  acids  inhibit  further  bile  acid   synthesis.     FXR  as  a  Bile  Acid  Receptor   • The  orphan  receptor  FXR  is  most  highly  expressed  in  tissues  where  bile  acids  function  (ie:  the  liver  and   intestines)   o Found  that  FXR  is  activated  by  the  primary  bile  acid   chenodeoxycholic  acid.   • Bile  Acids:   o Produced  in  the  liver,  secreted  into  bile  ducts  and  transported  to  the  small  intestine.   o They  are  not  simply  cholesterol   breakdown  products   o Important  for  two  reasons:   § They  represent  solubilized  excretable  forms  of  cholesterol   § Since  they  are  both  hydrophobic  and  hydrophilic  in  character,  bile  acids  function  to   facilitate  absorption  of  fats  and  fat -­‐soluble  vitamins  in  the  intestine.     Evidence  that  FXR  is  a  Bona  Fide  Bile  Acid  Receptor   1. Bile  acid-­‐bound  FXR  represses  expression  of  CYP7A  gene,  which  encodes  the  rate -­‐limiting  enzyme  in   cholesterol  metabolism  to  bile  acids,   thus  providing  a  molecular  mechanism  for  the  observed   feed-­‐back   mechanism  by  which  bile  acids  regulate  cholesterol  metabolism  (and  in  turn  bile  acid  production)   2. Elevated  bile  acid  levels  were  known  to  induce  expression  of   intestinal  bile  acid  binding  protein  (IBABP).     a. Bile  acid-­‐  bound  FXR  can  activate  transcription  of  the  IBABP  gene  in  the  intestine.     Identifying  Genes  Whose  Transcription  is  Regulated  by  Steroid  and  Related  Hormones   • Techniques  are  now  available  for  identifying  on  a  large  scale  (thousands  at  a  time)  genes  whose   transcription  is  regulated  by  nuclear  receptors.   o This  has  provided  novel  and  unexpected  insights  into  the  physiological  processes  regulated  by   nuclear  receptors.   • **not  on  the  exam**     DNA  Microarrays   • In  a  microarray  experiment,  purified   mRNAs  from  cells  isolated  under  specific  physiologica l  conditions  are   converted  into  fluorescent-­‐tagged  DNA  sequences  that  are  used  to  probe  microarrays.     • Microarrays  are  arrays  of  DNA  sequences  that  ar e  complementary  to  sequences  of  genes  transcribed  into   mRNAs.  When  a  fluorescent  probe  finds  its  complementary  sequence  on  the  microarray,  it  hybridizes  to  the   microarray.     • The  strength  of  the  resulting  fluorescent  signal  is  proportional  to  the  abundance  of  the  corresponding   mRNA.  In  this  way,  gene  expression  can  be  monitored  tens  of  thousands  of  genes  at    time. • **  Note:  will  not  be  tested  on  how  microarrays  work  on  the  exam **         2   WEEK  3   New  Insights  into  Vitamin  D  Physiology   1,25-­‐dihydroxyvitamin  D3  Biosynthesis   • Provitamin  D3  (7-­‐dihydocholesterol)  gets  converted  to   Vitamin  D3  in  the  skin  by  sufficient  levels  of  UV-­‐B  rays   o Ergosterol  in  fungi  has  the  same  background  and   will  go  through  the  same  cleavage  to  give  Vitamin  D2   § So,  vitamin  D3  comes  from  animals  and   vitamin  D2  from  Fungi   • This  undergoes  25-­‐hydroxylation  in  the  liver  to  yield  25-­‐ hydroxyvitamin  D3  (this  is  the  MAJOR  CIRCULATING  FORM )   • 1-­‐hydroxylation  in  Peripheral  Tissues  (including  skin)  yields   1,25  dihydroxyvitamin  D3   o This  is  the  HOROMONALLY  ACTIVE  FORM   o The  1-­‐hydroxylation  reaction  (kidney)  is  stimulated  by  Parathyroid  hormone  (PTH)   § We  now  know  that  this  reaction  can  occur  in  many  organs  other  than  the  kidney,  and  the   rate  in  these  tissues  will  not  be  regulated  by  calcium  homeostatic  inputs   • This  form  can  now  interact  with  the  Vitamin  D  Receptor   • Vitamin  D  Winter  refers  to  the  time  of  year  such  that  the  sun  is  low  enough  and  there  is  basically  no  UVB   reaching  the  earth  –  and  no  Vitamin  D3  is  produced.    In  Montreal,  we  have  roughly  6  months  a  year.   o Many  of  major  population  centers  in  Europe  are  more  northernly.  Scandinavian  countries   supplement  with  cod-­‐liver  oil  to  combat  vitamin  D3  deficiency.   o In  places  like  Saudi  Arabia,  where  the  sun  is  very  strong  and  temperatures  keep  people  in  doors  or   covered  up,  vitamin  D  deficiency  is  a  problem  as  well.   o Higher  altitude  will  lower  amount  of  time  in  Vit.  D3  winter.     • Levels  of  Major  Circulating  Vitamin  D  Metabolite,  25 -­‐hydroxyvitamin  D3,  are  different  in   African  and  Caucasian  Americans     o The  mean  levels  of  circulating  metabolites  will  vary  depending  on  the  time  of  year     o Caucasians  have  significantly  higher  levels  of  Serum  25D3       Three  Types  of  Diseases  Demonstrating  North -­‐South  Gradients   1. Certain  types  of  cancers  (in  particular  digestive  ca ncers  and  leukemias)   a. Rates  of  colon  cancer  in  the  USA  in  white  males  over  25  years  of  study   i. In  the  North  (excluding  mountainous  regions)  there  are  higher  rates  of  colon  cancer   compared  to  the  south.   ii. Seems  to  be  some  concordance  between  surface  UV -­‐B  levels  and  colon  cancer   iii. 1,25  D  does  have  some  anti -­‐cancer  properties  in  the  digestive  tract,  although  other  factors   must  be  considered  in  the  above  correlation   2. Autoimmune  diseases:  e.g.  MS,  and  Crohn’s  Disease   a. Clear  links  between  MS  and  type  I  diabetes  and  vitami n  D  deficiency   b. If  children  are  deficient  in  early  years,  there  is  an  increased  likelihood  of  disease  later  in  life   3. Infectious  Diseases   a. Considering  TB  infections,  noticed  that  country  populations  had  fewer  cases  than  in  the  city   b. Established  an  indirect  link  between  exposure  to  sunlight  and  likelihood  of  TB  infection   i. TB  replicates  in  macrophages.  If  treated  with  1,25  D  there  was  some  effect  on  TB  viability.   • Macrophages  become  responsive  to  24D3  after   detecting  the  presence  of  bacterial  cell  wall   (BCW)   components.  Innate  Immune  detection  of  infectious  agents  leads  to  expression  of   cyp27B1  mRNA  that   encodes  1-­‐hydroxylase  enzyme.  This  makes  the  cells  responsive  to  circulating  vitamin  D.   • Treatment  of  cells  with  1,25  dihydroxyvitamin  D3  induces  secreti on  of  antimicrobial  peptides  that  can  combat   E.  coli  and  P.  aeruginosa  growth.   • This  is  clinically  significant  considering  the  correlation  between  Afr.  Americans  and  Caucasians  above.   • Cells  incubated  with  serum  from  AA  and  C  were  compared.  AMP  response  is  g reatly  reduced  in  serum  from   A.A.  Therefore,  there  is  a   correlation  between  UVB  exposure/circulating  levels  of  25 -­‐D/  AMP  levels.     3   WEEK  3   Wednesday,  January  1 9 ,  2011   PHGY  210   Dr.  Lauzon   RESPIRATION    Function  of  Respiration:   • Primary  Function  of  Respiration  is   gas  exchange   • Inspiration:  air  rich  in2  O  is  inhaled  into  the  lungs   • Expiration:  CO 2 produced  during  oxidative  processes  of  the  body  is  exhaled  from  the  lungs   o Both  gases  are  transported  by  blood,  therefore,  both  cardiovascular  and  respiratory  systems  are   involved  in  the  process  of  respiration.       The  Respiratory  Tract   • Starts  at  the  nose/mouth   o Advantage  of  breathing  through  the  nose  is  that  big  particles  air   will  be  filtered  out   • Air  then  passes  into  the   pharynx  (passageway  for  air  and  food)   • The  vocal  cords  are  located  at  the   larynx   • At  this  point,  airway  splits  into  the  trachea  and  the  esophagus.   • The  trachea  only  passes  air  and  splits  into  two  main   bronchi.  These  then   split  into  smaller  and  shorter  bronchi  resulting  in  terminal   alveoli.   • At  these  alveolar  sacks,  gas  exchange  will  occur.   o Alveoli  are  surrounded  by  capillaries  that  allow   interaction  with  the  cardiovascular  system.   • The  RIGHT  main  bronchus  will  split  into  three   lobar  bronchi  that   direct  to  the  different  lobes  of  the  lung   o Humans:  3  lobes  in  the  right  lung  and  2  lobes  in  the  left     o In  mice,  there  are  3  lobes  on  either  side,  therefore,  the   distribution  of  lobes  is  species  dependent   • The  thorax  and  abdomen  are  separated  by  the   diaphragm  muscle.   This  is  the  main  muscle  involved  in  respirat ion.   • The  intercostal  muscles  are  found  between  ribs.     Pleural  Space   • There  is  a  space  between  the  lung  and  the  chest  cavity.     • The  visceral  pleura  is  the  outside  surface  of  the  lung,  and  the   membrane  covering  the  inside  chest  cavity  is  the   parietal  pleura.   • The  pleural  space  is  the  region  between  these  two  pleura.   o Extremely  important  –  filled  with  a  small  amount  of  fluid  and  NOT  air.   • Think  of  the  lungs  as  being  covered  by  a  fluid  filled  balloon.     • The  fluid  serves  as  lubrication  to  reduce  friction  of  lung  movement  against  the   chest  wall.  Additionally,  it   mechanically  couples  the  lungs  to  the  chest  wall .   o This  attachment  is  necessary  to  breathing   –  as  the  chest  expands,  the   chest  cavity  and  lungs  will  enlarge.  This  reduces  pressure  causing   inspiration  to  fill  the  lungs.   • Mechanical  coupling  between  chest  and  lungs  considering  the   pneumothorax   o If  a  hole  is  punctured  through  the  chest  cavity  into  the  pleural  space  we  would  have  a   pneumothorax.  The  lungs  will  COLLAPSE  and  the  chest  would  EXPAND .  This  occurs  during  accidents.   § Does  not  imply  damage  to  lungs,  just  implies  alteration  of  pressure  in  the  pleural  space.   § In  pneumothorax,  the  lungs  are  no  longer  mechanically  coupled  to  the  chest  wall.   § Even  if  the  brain  signals  for  muscle  contraction  to  get  inspiration,  in  th is  case  it  will  not.   o However,  the  pleural  spaces  of  the  lungs  are  separate  from  each  other,  allowing  prolonged  survival   in  cases  where  one  lung  has  collapsed.     4   WEEK  3   Mechanical  Pump   • During  inspiration:    The  respiratory  muscles  contract,  increasing  the  size  of  the  chest   • The  diaphragm  also  contracts  (downwards)  increasing  the  longitudinal  size  of  the  chest  larger.   o It  also  increased  the  cross  section  of  the  chest  area  as  well.   • This  essentially  draws  the  sides  of  the  lungs  outwards  increasing  the  area  occupied  by  the  lungs.  The  result   is  a  low  pressure  area  in  the  lungs  that  draws  in  air  from  the  environment.     Subdivisions  of  the  Conducting  Airways  and  Terminal  Respiratory  Units   • At  a  certain  diameter,  the  dividing  bronchi  are  then  referred  to  as   bronchioles.  These  continue  to  divide  until  the  terminal  bronchioles.   • The  Conducting  Zone  refers  to  the  initial  structures  of  the  airway:  Trachea,   Bronchi,  Bronchioles,  and  finally,  the   Terminal  Bronchioles   o This  zone  conducts  air  to  alveoli.   o Smooth  muscles  line  some  parts  of   the  conducting  zone.  They  are   involuntary  muscles  that  don’   • The  Respiratory  zone  is  where  alveoli  begin  to  appear  in  the  wall  of  the   airway.  At  this  point,  we  have   respiratory  bronchioles.   o The  alveolar  ducts  are  further  along  the  pathway  and  are  simply   ducts  lined  by  many  alveoli.   o Finally,  we  have  Alveolar  sacs  that  are  composed  entirely  of  alveoli.   § This  is  where  gas  exchange  occurs.   • The  functional  part  of  the  lungs  where  gas  exchange  occurs  is  also  called  the   acinus     The  4  Main  Functions  of  the  Conducting   Airways   1. Defense  against  bacterial  infection  and  foreign  particles   a. The  epithelial  lining  of  the  bronchi  has   cilia     b. Epithelial  glands  secrete  mucous  that  lines  the  respiratory  passages  down  to  the  bronchioles.   i. Foreign  particulates  are  trapped  in  the  mucous   and  beaten  to  the  pharynx  by  cilia   c. Note:  cilia  are  paralyzed  by  nicotine   –  thus,  smokers  get  accumulation  of  mucous   2. Condition  Air  –  warm  and  moisten  inhaled  air  to  prevent  damage  to  cells   a. Blood  vessels  surrounding  airways  will  dilate  to  warm  up  air   3. Sound  and  Speech  –  produced  by  movement  of  air  over  the  vocal  cords   4. Regulation  of  Air  Flow     a. Smooth  muscle  around  the  airways  may  contract  or  relax  to  alter  resistance  to  air  flow   b. In  asthmatic  patients,  the  smooth  muscle  contracts  making  it  difficult  to  breathe     Function  of  the  Respiratory  Zone   • The  respiratory  zone  is  the   site  of  gas  exchange  between  air
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