Soya phytoestrogens, genistein and daidzein, decrease apolipoprotein B secretion from HepG2 cells through multiple mechanisms

Abstract

Diets containing the soya-derived phytoestrogens, genistein and daidzein, decrease plasma cholesterol in humans and experimental animals. The mechanisms responsible for the hypocholesterolaemic effects of these isoflavones are unknown. The present study was conducted to determine if genistein and daidzein regulate hepatocyte cholesterol metabolism and apolipoprotein (apo) B secretion in cultured human hepatoma (HepG2) cells. ApoB secretion was decreased dose-dependently by up to 63% and 71% by genistein and daidzein (100 microM; P<0.0001) respectively. In contrast, no effect on apoAI secretion was observed. Cellular cholesterol synthesis was inhibited 41% by genistein (100 microM; P<0.005) and 18% by daidzein (100 microM; P<0.05), which was associated with significant increases in 3-hydroxy-3-methylglutaryl-CoA reductase mRNA. Cellular cholesterol esterification was decreased 56% by genistein (100 microM; P<0.04) and 29% by daidzein (100 microM; P<0.04); however, mRNA levels for acyl-CoA:cholesterol acyltransferase (ACAT) 1 and ACAT2 were unaffected. At 100 microM, both isoflavones equally inhibited the activities of both forms of ACAT in cells transfected with either ACAT1 or ACAT2. Genistein (100 microM) and daidzein (100 microM) significantly decreased the activity of microsomal triacylglycerol transfer protein (MTP) by 30% and 24% respectively, and significantly decreased MTP mRNA levels by 35% and 55%. Both isoflavones increased low-density lipoprotein (LDL)-receptor mRNA levels by 3- to 6-fold (100 microM; P<0.03) and significantly increased the binding, uptake and degradation of (125)I-labelled LDL, suggesting that enhanced reuptake of newly secreted apoB-containing lipoproteins contributed to the net decrease in apoB secretion. These results indicate that genistein and daidzein inhibit hepatocyte apoB secretion through several mechanisms, including inhibition of cholesterol synthesis and esterification, inhibition of MTP activity and expression and increased expression of the LDL-receptor.

Identification of the Flavonoid Luteolin as a Repressor of the Transcription Factor Hepatocyte Nuclear Factor 4α

“…It has been reported that MTP inhibitor treatment is associated with increased degradation of the apoB protein due to its incomplete lipidation (25). Consistent with this, treatment with genistein and naringenin decreased intracellular apoB protein levels and apoB secretion (23,24). In the present study, the 3-h luteolin treatment caused a reduction of intracellular apoB protein levels in HepG2 cells, which was not accompanied by a reduction of apoB mRNA expression, although apoB secretion was reduced (Fig.…”

“…There is evidence that genistein (isoflavone) and naringenin (flavanone) reduce the gene expression and activity of MTP, thereby inhibiting apoB secretion from HepG2 cells (23,24). In the present study, these flavonoids did not suppress the MTP promoter activity.…”

Effect of 3-month treatment of children and adolescents with familial and polygenic hypercholesterolaemia with a soya-substituted diet

“…The approximate 13 % decrease in apo B paralleling levels of TC and LDL-C in our patients is in accordance with data showing that the soya phyto-oestrogens genistein and daidzein decrease apo B secretion from HepG2 cells through multiple mechanisms by lowering cholesterol synthesis, cholesterol esterification, microsomal TAG transfer protein, and enhancing LDL-receptor activity 28 . Moreover, soya protein has been suggested to act as a strong antioxidant 29 .…”

Effect of genistein on cholesterol metabolism-related genes in a colon cancer cell line

“…Factors that up-regulate LDL receptor gene include estrogen and phytoestrogen in HepG2 cells and in rat liver [7,13,15]. Moreover the inhibition of mevalonate synthesis may be exerted by plant isoprenoid and genistein on experimental breast cancer [16].…”

“…Moreover the inhibition of mevalonate synthesis may be exerted by plant isoprenoid and genistein on experimental breast cancer [16]. Genistein has been also shown to decrease cholesterol synthesis in cultured HepG2 [7] and inhibits HMG-CoA reductase activity in MCF-7 human breast cancer cells [17]. It has been suggested that the soy proteins enhance the expression of the LDL receptor in cultured human hepatoma cells [26], animals, and hypercholesterolemic Type 2 diabetic patients [24,25].…”