Genistein and daidzein influence lipid metabolism in human and murine cells via liver X receptor

Liver X receptors (LXRs) are nuclear hormone receptors which are involved in the regulation of cholesterol and lipid metabolism. In mice, soy isoflavone consumption reduces hepatic lipid accumulation, however, it is not clear whether these effects are mediated via LXR along with other regulatory factors. We therefore investigated whether the regulation of lipid‐related gene expression by soy isoflavones was via the involvement of LXR. Study 1: HepG2 cells were cultured with or without 30μM genistein. After 24h, RNA was isolated and gene expression was determined using RT‐PCR. Genistein treatment significantly increased the relative mRNA levels of the following: the rate‐limiting enzyme for fatty acid β‐oxidation, carnitine palmitoyltransferase‐1α (CPT1α; 1.5‐fold); the expression of oxidative‐stress related NAD(P)H dehydrogenase [quinone] 1 (NQO1; 1.3 fold); the phase II enzyme, glutathione S‐transferase theta‐2 (GSTT2; 1.5 fold); ATP‐binding cassette transporter ABCA1, which mediates the efflux of cholesterol and phospholipids to lipid‐poor apolipoproteins (ABCA1; 1.4 fold); and acetyl‐CoA carboxylase alpha, which catalyzes the rate‐limiting step in fatty acid synthesis (ACACA; 1.2 fold) (all P<0.05). However, the expression of other genes such as cytochrome P450 family 8 subfamily B member 1 (CYP8B1), heme oxygenase 1 (HMOX‐1), and Apolipoprotein A (APOA) was not significantly changed. Study 2: Mouse embryonic fibroblast (MEF) cells and MEF cells knocked‐in with LXRs (MEF+) were used to determine the dependence of LXRs on lipid accumulation as influenced by genistein. MEF and MEF+ cells were exposed to genistein (40μM), daidzein (40μM), or the LXR agonist TO0901713 (2μM). The relative expression of mRNAs for sterol regulatory element‐binding protein 1a (Srebp1a), Abca1 and Stearoyl‐CoA desaturase‐1 (Scd1) were determined by RT‐PCR. We found that in MEF+ cells, Srebp1a, Abca1 and Scd1 gene expression was significantly increased in agonist‐and genistein‐treated cells. Incubation of MEF cells not expressing LXRs with genistein or TO0901713 had no effect, suggesting the effect of genistein on Srebp1a, Abca1 and Scd1 gene expression was via LXR action. Presently, on‐going studies are utilizing transient transfection assays using LXR expression vectors and LXRE‐regulated lucifierase reporter vectors to further confirm the effect of isoflavones on LXR and donwstream gene expression. Our data suggest that soy isoflavones stimulate the activation of LXRs, resulting in metabolic changes in cholesterol and lipid metabolism. Although other mechanisms are most likely involved, we suggest that LXR plays a role in isoflavone regulation of gene expression. Support or Funding Information Oregon Agricultural Research Foundation