Regulation of the expression of hepatic lipolysis stimulated lipoprotein receptor: roles of docosahexaenoic acid and peroxisome proliferator-activated receptor alpha

Abstract : Lipolysis stimulated lipoprotein receptor (LSR) plays an important role in the clearance of ApoB/ApoE containing triglyceride-rich lipoproteins during postprandial phase. In this study, we demonstrated that in vitro treatment of mouse hepatoma cells, Hepa 1-6, with docosahexaenoic acid (DHA) led to an increase in LSR protein levels as well as its activity. Furthermore, the mice placed on the diet supplemented with DHA showed an increase in hepatic LSR protein. However, the mRNA levels remained unchanged in both in vitro and in vivo studies, suggesting that DHA enrichment may result in changes in LSR microenvironment that could affect its anchorage at the surface of cell membrane. Specific peroxisome proliferator response elements were identified in the upstream region of human, mouse and rat lsr gene by in silico analysis. We therefore sought to determine the role of the transcription factor, peroxisome proliferator-activated receptor (PPAR[alpha]), in LSR regulation. In vitro pharmacological studies using PPAR[alpha]-selective agonist and antagonist agents demonstrated that PPAR[alpha] is indeed involved in the transcriptional regulation of LSR expression. Furthermore, qPCR array analysis revealed the downregulation of PPAR[alpha] and various genes involved in hepatic lipid metabolism in LSR+/- mice on standard and high-fat diets. In conclusion, these studies show that the hepatic LSR activity is controlled by dietary factors that can activate various pathways involved in regulating lipid homeostasis, therefore representing LSR as a potential target for either nutritional or therapeutic strategies towards the prevention or treatment of dyslipidemia
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Samina Akbar. Regulation of the expression of hepatic lipolysis stimulated lipoprotein receptor: roles of docosahexaenoic acid and peroxisome proliferator-activated receptor alpha. Food and Nutrition. Université de Lorraine, 2013. English. ⟨NNT : 2013LORR0288⟩. ⟨tel-01750639⟩

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