title: Triglyceride-rich lipoprotein regulates APOB48 receptor gene expression in human THP-1 monocytes and macrophages.
abstract: The postprandial metabolism of dietary fats implies that the production of TG-rich lipoproteins (TRL) contributes to the progression of plaque development. TRL and their remnants cause rapid receptor-mediated monocyte/macrophage lipid engorgement via the cell surface apoB48 receptor (apoB48R). However, the mechanistic basis for apoB48 receptor (APOB48R) regulation by postprandial TRL in monocytes and macrophages is not well established. In this study, we investigated the effects of postprandial TRL from healthy volunteers on the expression of APOB48R mRNA and lipid uptake in human THP-1 monocytes and THP-1-derived macrophages. The expression of APOB48R mRNA was upregulated in THP-1 monocytes, but downregulated in THP-1-derived macrophages when treated with postprandial TRL (P < 0.05), in a dose- and time-dependent manner. TG and free cholesterol were dramatically increased in THP-1-derived macrophages (140 and 50%, respectively; P < 0.05) and in THP-1 monocytes (160 and 95%, respectively; P < 0.05). This lipid accumulation was severely decreased (~50%; P < 0.05) in THP-1-derived macrophages by small interfering RNA (siRNA) targeting of APOB48R. Using PPAR and retinoid X receptor (RXR) agonists, antagonists, and siRNA, our data indicate that PPARα, PPARγ, and RXRα are involved in postprandial TRL-induced APOB48R transcriptional regulation. Co-incubation with acyl-CoA synthetase or acyl-CoA:cholesterol acyltransferase inhibitors potentiated the effects of postprandial TRL on the expression of APOB48R mRNA in THP-1 monocytes and THP-1-derived macrophages. Our findings collectively suggest that APOB48R represents a molecular target of postprandial TRL via PPAR-dependent pathways in human THP-1 monocytes and macrophages and advance a potentially important link between postprandial metabolism of dietary fats and atherogenesis.
authors.affiliation: Laboratory of Cellular and Molecular Nutrition, Instituto de la Grasa, CSIC, Seville, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Bermudez
authors.forename: Sergio
authors.initials: S
authors.lastname: Lopez
authors.forename: Lourdes M
authors.initials: LM
authors.lastname: Varela
authors.forename: Almudena
authors.initials: A
authors.lastname: Ortega
authors.forename: Yolanda M
authors.initials: YM
authors.lastname: Pacheco
authors.forename: Wenceslao
authors.initials: W
authors.lastname: Moreda
authors.forename: Rafael
authors.initials: R
authors.lastname: Moreno-Luna
authors.forename: Rocio
authors.initials: R
authors.lastname: Abia
authors.forename: Francisco J G
authors.initials: FJ
authors.lastname: Muriana
mesh_terms: D002460:Cell Line; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008074:Lipoproteins / Q000737:chemistry / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism*; D047493:PPAR alpha / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D019518:Postprandial Period; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D018110:Receptors, Lipoprotein / Q000235:genetics / Q000378:metabolism*; D047490:Retinoid X Receptor alpha / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000737:chemistry / Q000378:metabolism*
chemical_list: D005230:Fatty Acids, Nonesterified; D008074:Lipoproteins; D047493:PPAR alpha; D047495:PPAR gamma; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018110:Receptors, Lipoprotein; D047490:Retinoid X Receptor alpha; D014280:Triglycerides; C411291:apo B48 receptor