The Molecular Mechanisms Involved in Lipid Metabolism During Low Intensity Exercise
University of Wales
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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 10,000 steps, 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 1.28 mmol/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: 1.8 0.9 fold; 8 weeks: 4.3 1.9 fold) was observed, which was reinforced by increased PPARγ DNA-binding activity post exercise (pre-exercise: 0.22 0.09 OD units; post-exercise: 1.13 0.29 OD units. A significant increase in gene expression was observed for the oxLDL scavenger receptor CD36 (4 weeks: 3.8 0.6 fold; 8 weeks: 2.7 0.5 fold). LXRα (8 weeks: 3.5 0.8 fold) and two LXRα regulated genes involved in RCT, namely ABCA1 and ABCG1 were significantly upregulated after eight weeks of exercise (8 weeks: ABCA1: 3.46 0.56 fold; ABCG1: 3.06 0.47 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.
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