Nuclear receptors, such as liver X receptors (LXRs) and sterol regulatory element-binding proteins (SREBPs), are key regulators of lipogenic genes, including fatty acid synthase (FASN). It has been reported that several oxycholesterols (OCs) act as LXR ligands; however, it is unclear whether all OC molecular species act as ligands. We previously demonstrated that the absorption rate of dietary 6-ketocholestanol (6-keto), an oxycholesterol, is the highest of all the OCs using thoracic lymph duct-cannulated rats. However, limited information is available about the physiological significance of 6-keto. In this study, we investigated whether treatment with 6-keto increases intracellular triacylglycerol (TAG) levels through up-regulation of lipogenic gene expression in HepG2 cells. 6-Keto treatment significantly reduced intracellular TAG levels through down-regulation of lipogenic genes including FASN. Although 6-keto significantly suppressed FASN gene promoter activities, the action was completely diminished when mutations were present in the SREBP promoter site. TO901317 (TO) significantly increased FASN gene promoter activities, whereas simultaneous treatment with TO and 6-keto significantly reduced this activity. We also compared the effects of several OCs that are oxidized at the carbon-6 and -7 in the B-ring of cholesterol on FASN gene promoter activities. Similar to 6-keto, 6α-OH and 6β-OH significantly reduced the activity of the FASN gene promoter, which suggests that oxidation of carbon-6 in the B-ring may play an important role in the reduction of FASN expression. Our results indicate that 6-keto suppresses lipid accumulation by decreasing FASN gene expression through SREBP-dependent regulation in HepG2 cells.

中文翻译：

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6-酮胆甾醇通过SREBP依赖性调控HepG2细胞中的FASN基因表达来抑制脂质蓄积。

核受体，例如肝X受体（LXR）和固醇调节元件结合蛋白（SREBP），是脂肪形成基因的关键调节剂，包括脂肪酸合酶（FASN）。据报道，几种氧胆固醇（OC）充当LXR配体。然而，尚不清楚是否所有的OC分子物种都充当配体。我们先前证明，使用胸腔淋巴导管插管的大鼠，饮食中的6-酮胆固醇（6-酮）（一种氧胆固醇）的吸收率是所有OC中最高的。但是，关于6-酮的生理意义的信息有限。在这项研究中，我们调查了6-酮处理是否通过上调HepG2细胞中生脂基因表达来增加细胞内三酰基甘油（TAG）水平。6-酮治疗通过下脂基因（包括FASN）的下调显着降低了细胞内TAG水平。尽管6-酮显着抑制了FASN基因启动子的活性，但当SREBP启动子位点存在突变时，该作用完全减弱。TO901317（TO）显着增加了FASN基因启动子的活性，而同时使用TO和6-酮处理则显着降低了该活性。我们还比较了在胆固醇B环的碳6和-7处被氧化的几种OC对FASN基因启动子活性的影响。与6-酮类似，6α-OH和6β-OH显着降低了FASN基因启动子的活性，这表明B环中碳-6的氧化可能在降低FASN表达中起重要作用。