The peroxisome proliferator activated receptors (PPARs) are a group of transcription factors belonging to the nuclear receptor superfamily. Since most target genes of either PPARs are implicated in lipid and glucose metabolism, regulation by PPARs could be used as a screening tool to identify novel genes involved in lipid or glucose metabolism. Here, we identify Adtrp, a serine hydrolase enzyme that was reported to catalyze the hydrolysis of fatty acid esters of hydroxy fatty acids (FAHFAs), as a novel PPAR-regulated gene. Adtrp was significantly upregulated by PPARα activation in mouse primary hepatocytes, liver slices, and whole liver. In addition, Adtrp was upregulated by PPARγ activation in 3L3-L1 adipocytes and in white adipose tissue. ChIP-SEQ identified a strong PPAR binding site in the immediate upstream promoter of the Adtrp gene. Adenoviral-mediated hepatic overexpression of Adtrp in diet-induced obese mice caused a modest increase in plasma non-esterified fatty acids but did not influence diet-induced obesity, liver triglyceride levels, liver lipidomic profiles, liver transcriptomic profiles, and plasma cholesterol, triglycerides, glycerol, and glucose levels. Moreover, hepatic Adtrp overexpression did not lead to significant changes in FAHFA levels in plasma or liver and did not influence glucose and insulin tolerance. Finally, hepatic overexpression of Adtrp did not influence liver triglycerides and levels of plasma metabolites after a 24h fast. Taken together, our data suggest that despite being a PPAR-regulated gene, hepatic Adtrp does not seem to play a major role in lipid and glucose metabolism and does not regulate FAHFA levels.

中文翻译：

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肝 ADTRP 过表达不影响脂质和葡萄糖代谢

过氧化物酶体增殖物激活受体 (PPAR) 是一组属于核受体超家族的转录因子。由于任一 PPARs 的大多数靶基因都与脂质和葡萄糖代谢有关，因此 PPARs 的调节可用作筛选工具来鉴定参与脂质或葡萄糖代谢的新基因。在这里，我们确定 Adtrp，一种丝氨酸水解酶，据报道催化羟基脂肪酸的脂肪酸酯 (FAHFA) 的水解，作为一种新型的 PPAR 调节基因。Adtrp 在小鼠原代肝细胞、肝切片和全肝中被 PPARα 激活显着上调。此外，在 3L3-L1 脂肪细胞和白色脂肪组织中，Adtrp 被 PPARγ 激活上调。ChIP-SEQ 在 Adtrp 基因的直接上游启动子中鉴定了一个强 PPAR 结合位点。在饮食诱导的肥胖小鼠中，腺病毒介导的 Adtrp 肝脏过度表达导致血浆非酯化脂肪酸适度增加，但不影响饮食诱导的肥胖、肝脏甘油三酯水平、肝脏脂质组学特征、肝脏转录组学特征和血浆胆固醇、甘油三酯、甘油和葡萄糖水平。此外，肝脏 Adtrp 过表达不会导致血浆或肝脏中 FAHFA 水平的显着变化，并且不会影响葡萄糖和胰岛素耐受性。最后，在禁食 24 小时后，Adtrp 的肝脏过表达不影响肝脏甘油三酯和血浆代谢物的水平。总之，我们的数据表明，尽管是 PPAR 调节的基因，但肝脏 Adtrp 似乎在脂质和葡萄糖代谢中并不起主要作用，也不调节 FAHFA 水平。