The effects on markers of cellular stress and RAGE splicing in cellular models and in subjects receiving dietary CLA supplementation

 The  dietary  lipid  Conjugated  Linoleic  Acid  (CLA)  has  been  the  subject  of  a  large body  of  research  in  relation  to  its anti-inflammatory  and  immunoregulatory  role  in many  cell  types  and  animal  models.This  study  aimed  to investigate  the  effect  of a mixtureof the 9:11 and 10:12 isomers of CLAas well as the effect of the 9:11 isomer aloneon  the  human  monocytic  cell-line  THP-1  cells  and  human  endothelial  cells (HUVEC). The effect of supplementation with 2g/day CLA (a 50:50 mixture of 9:11 and  10:12  CLA)  and  9:11  CLA  in  a  cross-over  trial  in  subjects  with  metabolic syndrome  was  also  investigated.  Neither  CLA  nor  9:11  CLA  demonstrated  any significant endoplasmic reticulum stress or induced apoptosis when cells were treated with  the  lipids  over  a  concentration  range  of  20-200μM. Both  lipids  were  able  to upregulate  gene  expression  of  the  nuclear  transcription  factor  PPARγ  in  both  cell types, with CLA having the most marked effect. A significant increase in the PPARγ dependant gene CD36 was also observed and a significant increase in PPARαmRNA was  seen  with  CLA.However,  no  significant  increase  in  thePPARα  dependant CXCL2  gene  was  observed.  PPAR  activity  in  these  cells  did  not  appear  to  be mediated  by  the  induction  of  endogenous  ligands  by  Cycloxygenase-2.  Both  lipids were  capable  of  upregulating  another  transcription  factor  LXRα,  suggesting  animportant  role  for  both  lipids in  cholesterol  homeostasis.Both  CLA  and  9:11  CLA increased  mRNA  expression  for  the  receptor  for  advanced  glycated  end-products (RAGE)   and   induced   solubilisation   of  the   receptor   that   was   not   mediated   by increasing   activation   of the metalloproteinase   enzyme   ADAM10.   There   was significant  induction  ofRAGE splice  variants secretion in  particular  esRAGEafter CLA  supplementation.The  clinical  trial  demonstrated  that dietary  supplementation with  both  isomers  induced increased  sRAGE  secretion,  and  improved  markers  of endothelial function and diastolic blood pressure. Improved platelet function was also observed and a non-significant but beneficial trend was observed for HDL-cholesterol and LDL-cholesterol. Multiregression analysis would suggest that the most significant predictor  of  the  reduction  in  DBP  was  the  increase  in  sRAGE  secretion  induced  by both CLA and 9:11 CLA.In conclusion,this study would support a beneficial role for CLA  and  its  9:11  isomer  in  mediating  the  pro-atherogenic  effects  observed  in inflammatory disorders such as type 2 Diabetes Mellitus.