Modulation of hepatic lipoprotein synthesis and secretion by taxifolin, a plant flavonoid.
In the present study, the effects of taxifolin, a plant flavonoid, on lipid, apolipoprotein B (apoB), and apolipoprotein A-I (apoA-I) synthesis and secretion were determined in HepG2 cells. Pretreatment of cells with (+/-)-taxifolin led to an inhibition of cholesterol synthesis in a dose- and time-dependent manner, with an 86 +/- 3% inhibition at 200 microM observed within 24 h. As to the mechanism underlying this inhibitory effect, taxifolin was shown to inhibit the activity of HMG-CoA reductase by 47 +/- 7%. In addition, cellular cholesterol esterification, and triacylglycerol and phospholipid syntheses, were also significantly suppressed in the presence of taxifolin. ApoA-I and apoB synthesis and secretion were then studied by pulse-chase experiments. ApoA-I secretion was found to increase by 36 +/- 10%. In contrast, an average reduction of 61 +/- 8% in labeled apoB in the medium was apparent with taxifolin. This effect on secretion appeared not to be exerted at the transcriptional level. Rather, the effect on apoB secretion was found to be exerted in the early stages of apoB degradation and to be sensitive to dithiothreitol (DTT) and insensitive to N-acetyl-leucyl-leucyl-norleucinal, suggesting a proteolytic pathway involving a DTT-sensitive protease. Fractionation of secreted apoB revealed a slight shift in the distribution of secreted apoB-containing lipoproteins. Cholesteryl ester, rather than triacylglycerol, was shown to be the lipid that primarily regulated apoB secretion. In summary, our data suggest that taxifolin decreases hepatic lipid synthesis with a concomitant decrease and increase in apoB and apoA-I secretion, respectively.
Theriault
A
A
Division of Medical Technology, University of Hawaii, Honolulu, HI 96822, USA.
Wang
Q
Q
Van Iderstine
S C
SC
Chen
B
B
Franke
A A
AA
Adeli
K
K
D000924:Anticholesteremic Agents / Q000494:pharmacology; D016632:Apolipoprotein A-I / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D001055:Apolipoproteins B / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000096:biosynthesis; D004229:Dithiothreitol / Q000494:pharmacology; D044948:Flavonols; D006801:Humans; D006868:Hydrolysis; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D011794:Quercetin / Q000031:analogs & derivatives / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D014407:Tumor Cells, Cultured
D000924:Anticholesteremic Agents; D016632:Apolipoprotein A-I; D001055:Apolipoproteins B; D044948:Flavonols; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007976:Leupeptins; D012333:RNA, Messenger; C063261:acetylleucyl-leucyl-norleucinal; D002784:Cholesterol; D011794:Quercetin; C003377:taxifolin; D006903:Hydroxymethylglutaryl CoA Reductases; D004229:Dithiothreitol