Inhibition of ACAT by avasimibe decreases both VLDL and LDL apolipoprotein B production in miniature pigs

Burnett, John R.; Wilcox, Lisa J.; Telford, Dawn E.; Kleinstiver, Sandra J.; Barrett, P. Hugh R.; Newton, Roger S.; Huff, Murray W.

doi:10.1016/s0022-2275(20)33494-5

Cited by 72 publications

(13 citation statements)

References 65 publications

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“…The reduction of CEs putatively mediated by suppression of ACAT1 function might affect the packaging of CEs to nascent VLDL and thereby their secretion.In agreement with these data we previously reported that there was a reduction of CE/apoB ratio in plasma VLDL and LDL particles derived from ANGPTL3 LOF homozygote carriers compared with noncarrier subjects[9;22]. Decreases of VLDL and LDL were observed in pigs treated with avasimibe, an inhibitor of SOAT[60].…”

supporting

confidence: 88%

ANGPTL3 deficiency alters the lipid profile and metabolism of cultured hepatocytes and human lipoproteins

Ruhanen

Haridas

Minicocci

et al. 2020

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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supporting

confidence: 88%

ANGPTL3 deficiency alters the lipid profile and metabolism of cultured hepatocytes and human lipoproteins

Ruhanen

Haridas

Minicocci

et al. 2020

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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“…Inhibition of newly synthesized CEs catalyzed by ACAT has been shown to decrease apoB secretion in HepG2 cells (15,16,42,43), although this has not been a universal finding (15). Furthermore, we have previously shown, using in vivo kinetic studies in pigs (14,44,45), that inhibition of hepatic cholesterol esterifi-cation decreases hepatic apoB secretion. In the present study, the flavonoids decreased ACAT activity in HepG2 cells by 75-85%, which was associated with a 74 -82% reduction in apoB secretion.…”

Section: Discussionmentioning

confidence: 98%

Secretion of hepatocyte apoB is inhibited by the flavonoids, naringenin and hesperetin, via reduced activity and expression of ACAT2 and MTP

Wilcox¹,

Borradaile²,

Dreu

et al. 2001

Journal of Lipid Research

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211

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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 Ͻ 0.00001) or hesperetin (up to 74%, P Ͻ 0.002). Decreased apoB secretion was associated with reduced cellular cholesteryl ester mass. Cholesterol esterification was decreased, dose-dependently, up to 84% ( P Ͻ 0.0001) at flavonoid concentrations of 200 M. 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 Ͻ 0.001) by both flavonoids, whereas ACAT1 mRNA was unaffected. In addition, naringenin and hesperetin decreased both the activity ( ؊ 20% to ؊ 40%, P Ͻ 0.00004) and expression ( ؊ 30% to ؊ 40%, P Ͻ 0.02) of microsomal triglyceride transfer protein (MTP). Both flavonoids caused a 5-to 7-fold increase ( P Ͻ 0.02) in low density lipoprotein (LDL) receptor mRNA, which resulted in a 1.5-to 2-fold increase in uptake and degradation of 125 I-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. -Wilcox, L. J., N. M. Borradaile, L. E. de Dreu, and M. W. Huff. Secretion of hepatocyte apoB is inhibited by the flavonoids, naringenin and hesperetin, via reduced activity and expression of ACAT2 and MTP.

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“…The analysis of apoB cellular pulse-chase data by multicompartmental modeling, in this study, is a novel approach. We have previously used compartmental modeling for in vivo apoB kinetic studies (18,20,48). We now extend this technique to the analysis of apoB pulse-chase data in HepG2 cells.…”

Section: Discussionmentioning

confidence: 99%

Differential regulation of apolipoprotein B secretion from HepG2 cells by two HMG-CoA reductase inhibitors, atorvastatin and simvastatin

Wilcox

Barrett

Huff

1999

Journal of Lipid Research

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The concept that hepatic cholesterol synthesis regulates hepatocyte assembly and secretion of apoB-containing lipoproteins remains controversial. The present study was carried out in HepG2 cells to examine the regulation of apoB secretion by the HMG-CoA reductase inhibitor atorvastatin. ApoB accumulation in the media was decreased by 24% and 36% at 10 M ( P Ͻ 0.02) and 20 M ( P Ͻ 0.01) of atorvastatin, respectively. Atorvastatin inhibited HepG2 cell cholesterol synthesis by up to 96% ( P Ͻ 0.001) and cellular cholesteryl ester (CE) mass by 54% ( P Ͻ 0.001). Another HMG-CoA reductase inhibitor, simvastatin, decreased cellular cholesterol synthesis and CE mass by up to 96% ( P Ͻ 0.001) and 52% ( P Ͻ 0.001), respectively. However, in contrast to atorvastatin, simvastatin had no effect on apoB secretion. To characterize the reduction in apoB secretion by atorvastatin (10 M ), pulse-chase experiments were performed and the kinetic data were analyzed by multicompartmental modeling using SAAM II. Atorvastatin had no affect on the synthesis of apoB, however, apoB secretion into the media was decreased by 44% ( P ‫؍‬ 0.048). Intracellular apoB degradation increased proportionately ( P ‫؍‬ 0.048). Simvastatin (10 M ) treatment did not significantly alter either the secretion or intracellular degradation of apoB, relative to control. The kinetics of apoB degradation were best described by a rapidly and a slowly turning over degradation compartment. The effect of atorvastatin on apoB degradation was largely confined to the rapid compartment. Neither inhibitor affected apoB mRNA concentrations, however, both significantly increased LDL receptor and HMG-CoA reductase mRNA levels. Atorvastatin treatment also decreased the mRNA for the microsomal triglyceride transfer protein (MTP) by 22% ( P Ͻ 0.02). These results show that atorvastatin decreases apoB secretion, by a mechanism that results in an enhanced intracellular degradation of apoB. -Wilcox, L. J., P. H. R. Barrett, and M. W. Huff. Differential regulation of apolipoprotein B secretion from HepG2 cells by two HMG-CoA reductase inhibitors, atorvastatin and simvastatin.

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Inhibition of ACAT by avasimibe decreases both VLDL and LDL apolipoprotein B production in miniature pigs

Cited by 72 publications

References 65 publications

ANGPTL3 deficiency alters the lipid profile and metabolism of cultured hepatocytes and human lipoproteins

ANGPTL3 deficiency alters the lipid profile and metabolism of cultured hepatocytes and human lipoproteins

Secretion of hepatocyte apoB is inhibited by the flavonoids, naringenin and hesperetin, via reduced activity and expression of ACAT2 and MTP

Differential regulation of apolipoprotein B secretion from HepG2 cells by two HMG-CoA reductase inhibitors, atorvastatin and simvastatin

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