6B). Luciferase activity assay showed that deletion of all four potential LXRE sites had little effect on SREBP-1c-induced Thrsp promoter activity, but ablation of the proximal region containing the potential SRE site almost completely abolished promoter activity

(Fig. 6B). This finding suggests that the SRE site within the Thrsp promoter is responsible for SREBP-1c–induced up-regulation of Thrsp expression. It also suggests that SREBP-1 may be essential for basal Thrsp expression, which is consistent with the finding that basal levels of Thrsp expression were significantly lower in SREBP-1c−/− mice than in WT mice (Fig. 5C). By using the full-length Thrsp promoter (−2,931/+22 bp)-driven luciferase construct, we determined the effect

of TO901317 treatment and overexpression of LXR-α, SREBP-1, and SREBP-2 on luciferase activity. Reporter activity this website was not induced either click here by TO901317 treatment or by LXR-α overexpression (Fig. 6C). However, reporter activity was significantly increased by both SREBP-1c(N) and SREBP-2(N) overexpression, with SREBP-1c(N) being more potent than SREBP-2(N) (Fig. 6C). This finding is consistent with increased binding of SREBPs to the SRE site of the Thrsp promoter in TO901317-treated mouse liver (Fig. 5B). Together, these results demonstrate that LXR-induced Thrsp transcription

occurs by an SREBP-dependent mechanism. In the present study, we provide direct evidence that specific overexpression of Thrsp in livers of C57Bl/6 mice significantly promotes hepatic lipogenesis, and that hepatic knockdown of Thrsp markedly attenuates the fatty liver phenotype in db/db mice, suggesting that Thrsp is an important lipogenic factor in the liver. Hepatic Thrsp expression is induced by the LXR agonist, TO901317, which is mediated by LXR-α and dependent on 上海皓元医药股份有限公司 the downstream transcriptional factor, SREBP-1. Our findings suggest that Thrsp may be involved in LXR activator-induced fatty liver, and it may represent a therapeutic target for the treatment of NAFLD. Since Thrsp was discovered three decades ago, a number of studies have reported that it acts as a transducer of hormone-related and nutrient-related signals to genes involved in lipid metabolism.[11] Recently, accumulating evidence has suggested that Thrsp may also play an important role in the induction of lipogenic enzymes, particularly by carbohydrate feeding and thyroid hormone administration, with the biochemical mechanism uncharacterized.[11, 14] Some recent studies demonstrate that Thrsp may work as a cofactor regulating TR-dependent and p53-dependent transcriptional activation, providing a clue to its biochemical function.