Secretion of hepatocyte apoB is inhibited by the flavonoids, naringenin and hesperetin, via reduced activity and expression of ACAT2 and MTP
The citrus flavonoids, naringenin and hesperetin, lower plasma cholesterol in vivo. However, the underlying mechanisms are not fully understood. The ability of these flavonoids to modulate apolipoprotein B (apoB) secretion and cellular cholesterol homeostasis was determined in the human hepatoma cel...
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doaj-12a515d9e08c4a66a0daefaeb45f563c2021-04-27T04:40:23ZengElsevierJournal of Lipid Research0022-22752001-05-01425725734Secretion of hepatocyte apoB is inhibited by the flavonoids, naringenin and hesperetin, via reduced activity and expression of ACAT2 and MTPLisa J. Wilcox0Nica M. Borradaile1Linda E. de Dreu2Murray W. Huff3Departments of Medicine and Biochemistry and The John P. Robarts Research Institute, 4-16, University of Western Ontario, 100 Perth Drive, London, Ontario N6A 5K8, CanadaDepartments of Medicine and Biochemistry and The John P. Robarts Research Institute, 4-16, University of Western Ontario, 100 Perth Drive, London, Ontario N6A 5K8, CanadaDepartments of Medicine and Biochemistry and The John P. Robarts Research Institute, 4-16, University of Western Ontario, 100 Perth Drive, London, Ontario N6A 5K8, CanadaTo whom all correspondence should be addressed. e-mail:; Departments of Medicine and Biochemistry and The John P. Robarts Research Institute, 4-16, University of Western Ontario, 100 Perth Drive, London, Ontario N6A 5K8, CanadaThe citrus flavonoids, naringenin and hesperetin, lower plasma cholesterol in vivo. However, the underlying mechanisms are not fully understood. The ability of these flavonoids to modulate apolipoprotein B (apoB) secretion and cellular cholesterol homeostasis was determined in the human hepatoma cell line, HepG2. apoB accumulation in the media decreased in a dose-dependent manner following 24-h incubations with naringenin (up to 82%, P < 0.00001) or hesperetin (up to 74%, P < 0.002). Decreased apoB secretion was associated with reduced cellular cholesteryl ester mass. Cholesterol esterification was decreased, dose-dependently, up to 84% (P < 0.0001) at flavonoid concentrations of 200 μM. Neither flavonoid demonstrated selective inhibition of either form of acyl CoA:cholesterol acyltransferase (ACAT) as determined using CHO cells stably transfected with either ACAT1 or ACAT2. However, in HepG2 cells, ACAT2 mRNA was selectively decreased (−50%, P < 0.001) by both flavonoids, whereas ACAT1 mRNA was unaffected. In addition, naringenin and hesperetin decreased both the activity (−20% to −40%, P < 0.00004) and expression (−30% to −40%, P < 0.02) of microsomal triglyceride transfer protein (MTP). Both flavonoids caused a 5- to 7-fold increase (P < 0.02) in low density lipoprotein (LDL) receptor mRNA, which resulted in a 1.5- to 2-fold increase in uptake and degradation of 125I-LDL.We conclude that both naringenin and hesperetin decrease the availability of lipids for assembly of apoB-containing lipoproteins, an effect mediated by 1) reduced activities of ACAT1 and ACAT2, 2) a selective decrease in ACAT2 expression, and 3) reduced MTP activity. Together with an enhanced expression of the LDL receptor, these mechanisms may explain the hypocholesterolemic properties of the citrus flavonoids.http://www.sciencedirect.com/science/article/pii/S0022227520316345flavonoidsnaringeninhesperetinapoBmicrosomal triglyceride transfer proteinHepG2 cells |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Lisa J. Wilcox Nica M. Borradaile Linda E. de Dreu Murray W. Huff |
spellingShingle |
Lisa J. Wilcox Nica M. Borradaile Linda E. de Dreu Murray W. Huff Secretion of hepatocyte apoB is inhibited by the flavonoids, naringenin and hesperetin, via reduced activity and expression of ACAT2 and MTP Journal of Lipid Research flavonoids naringenin hesperetin apoB microsomal triglyceride transfer protein HepG2 cells |
author_facet |
Lisa J. Wilcox Nica M. Borradaile Linda E. de Dreu Murray W. Huff |
author_sort |
Lisa J. Wilcox |
title |
Secretion of hepatocyte apoB is inhibited by the flavonoids, naringenin and hesperetin, via reduced activity and expression of ACAT2 and MTP |
title_short |
Secretion of hepatocyte apoB is inhibited by the flavonoids, naringenin and hesperetin, via reduced activity and expression of ACAT2 and MTP |
title_full |
Secretion of hepatocyte apoB is inhibited by the flavonoids, naringenin and hesperetin, via reduced activity and expression of ACAT2 and MTP |
title_fullStr |
Secretion of hepatocyte apoB is inhibited by the flavonoids, naringenin and hesperetin, via reduced activity and expression of ACAT2 and MTP |
title_full_unstemmed |
Secretion of hepatocyte apoB is inhibited by the flavonoids, naringenin and hesperetin, via reduced activity and expression of ACAT2 and MTP |
title_sort |
secretion of hepatocyte apob is inhibited by the flavonoids, naringenin and hesperetin, via reduced activity and expression of acat2 and mtp |
publisher |
Elsevier |
series |
Journal of Lipid Research |
issn |
0022-2275 |
publishDate |
2001-05-01 |
description |
The citrus flavonoids, naringenin and hesperetin, lower plasma cholesterol in vivo. However, the underlying mechanisms are not fully understood. The ability of these flavonoids to modulate apolipoprotein B (apoB) secretion and cellular cholesterol homeostasis was determined in the human hepatoma cell line, HepG2. apoB accumulation in the media decreased in a dose-dependent manner following 24-h incubations with naringenin (up to 82%, P < 0.00001) or hesperetin (up to 74%, P < 0.002). Decreased apoB secretion was associated with reduced cellular cholesteryl ester mass. Cholesterol esterification was decreased, dose-dependently, up to 84% (P < 0.0001) at flavonoid concentrations of 200 μM. Neither flavonoid demonstrated selective inhibition of either form of acyl CoA:cholesterol acyltransferase (ACAT) as determined using CHO cells stably transfected with either ACAT1 or ACAT2. However, in HepG2 cells, ACAT2 mRNA was selectively decreased (−50%, P < 0.001) by both flavonoids, whereas ACAT1 mRNA was unaffected. In addition, naringenin and hesperetin decreased both the activity (−20% to −40%, P < 0.00004) and expression (−30% to −40%, P < 0.02) of microsomal triglyceride transfer protein (MTP). Both flavonoids caused a 5- to 7-fold increase (P < 0.02) in low density lipoprotein (LDL) receptor mRNA, which resulted in a 1.5- to 2-fold increase in uptake and degradation of 125I-LDL.We conclude that both naringenin and hesperetin decrease the availability of lipids for assembly of apoB-containing lipoproteins, an effect mediated by 1) reduced activities of ACAT1 and ACAT2, 2) a selective decrease in ACAT2 expression, and 3) reduced MTP activity. Together with an enhanced expression of the LDL receptor, these mechanisms may explain the hypocholesterolemic properties of the citrus flavonoids. |
topic |
flavonoids naringenin hesperetin apoB microsomal triglyceride transfer protein HepG2 cells |
url |
http://www.sciencedirect.com/science/article/pii/S0022227520316345 |
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