The molecular mechanisms involved in lipid metabolism during low intensity exercise

 An    important    molecular    mechanism    by    which    physical    activity    reduces cardiovascular  risk is  through  regulation  of  plasma  lipids.  This  study  aimed  to investigate  whether  low  intensity  exercise  modulates  monocytic  lipid  metabolism and the activity of the nuclear transcription factor Peroxisome Proliferators-Activated Receptor-γ  (PPARγ).  Furthermore,  this  study  aimed  to  elucidate  the  molecular signalling mechanisms induced through PPARγ activation.Thirty-four  sedentary  adults,  mean  age  45.6  ±  11.1  years,  participated  in  an  eight week  low  intensity  exercise  programme  consisting  of  walking  10,000steps,  three times  a  week.  Compared  to  controls,  there  was  a  significant  decrease  in  total cholesterol  (pre-exercise:  5.73 1.39  mmol/L;  post-exercise: 5.32 1.28mmol/L)and  a  significant  increase  in  high  density  lipoprotein  (pre-exercise:  1.46 0.47 mmol/L;  post-exercise:  1.56 0.50  mmol/L) after  the  exercise  programme.  There was also a significant increase in serum oxidised LDL (oxLDL) concentrations pre to post  exercise (0  weeks:  554 107ng/ml;  4weeks:  698 134ng/ml;  8weeks:  588 145ng/ml).A significant increase in leukocyte mRNA expression for PPARγ (4 weeks: 1.80.9 fold;  8weeks:  4.31.9  fold)was observed, which  was  reinforced  by  increased PPARγ  DNA-binding  activity post  exercise (pre-exercise:  0.220.09 OD units; post-exercise:  1.130.29 OD units. A  significant  increase  in  gene  expression  was observed for the oxLDL scavenger receptor CD36 (4 weeks: 3.80.6 fold; 8 weeks: 2.70.5  fold). LXR (8weeks:  3.50.8  fold) and two  LXRα  regulated  genes involved  in  RCT,  namely  ABCA1  andABCG1  were  significantly  upregulated  after eight  weeks  of  exercise (8  weeks: ABCA1: 3.460.56  fold; ABCG1:  3.060.47 fold). The  culmination  of in-vitro evidence  lead  to  the  postulation  of  a  two  pathway molecular mechanism associated with oxLDL stimulation of CD36, via PPARγ in monocytic cells. A „short-term‟ pathway (<24 hours), upregulates PPARγ (2 fold) via a  transient  ERK1/2  and  COX-2  dependent  mechanism.  Whereas  a  „long-term‟pathway (>24 hours), involves the direct upregulation of PPARγ via ligands within oxLDL,  which  is  ERK1/2  independent  but  still  COX-2  dependent.  Activation  of PPARγ enables direct DNA-binding with CD36,  facilitating the oxLDL to enter the cell,  via  CD36,  exacerbating  the  effect  and  promoting  the  cellular  clearance  of oxLDL. However, between 24 and 72 hours the „short-term‟ pathway is required to upregulate PPARγ via COX-2 and hence induces upregulation of CD36. It is possible that over several weeks  of low intensity  exercise the more rapid molecular pathway can be supplemented by PPARγ ligands present within oxLDL, and hence directly stimulate PPARγ gene transcription. In  conclusion  this  study  proposes  a novel molecular  mechanism for low  intensity exercise  induced  modulation of plasma  lipids  via  cellular  clearance  of  cholesterol that involves activation of the nuclear transcription factors PPARγ and LXRα.