Abstract：
Hepatic lipid metabolism is modulated by the circadian rhythm; therefore, circadian disruption may promote obesity and hepatic lipid accumulation. This study aims to investigate dietary pterostilbene (PSB) \'s protective effect against high-fat-diet (HFD)-induced lipid accumulation exacerbated by chronic jet lag and the potential role of gut microbiota therein. Mice were treated with a HFD and chronic jet lag for 14 weeks. The experimental group was supplemented with 0.25% (w/w) PSB in its diet to evaluate whether PSB had a beneficial effect. Our study found that chronic jet lag exacerbates HFD-induced obesity and hepatic lipid accumulation, but these adverse effects were significantly mitigated by PSB supplementation. Specifically, PSB promoted hepatic lipolysis and β-oxidation by upregulating SIRT1 expression, which indirectly reduced oxidative stress caused by lipid accumulation. Additionally, the PSB-induced elevation of SIRT1 and SIRT3 expression helped prevent excessive autophagy and mitochondrial fission by activating Nrf2-mediated antioxidant enzymes. The result was evidenced by the use of SIRT1 and SIRT3 inhibitors in in vitro studies, which demonstrated that activation of SIRT1 and SIRT3 by PSB is crucial for the translocation of PGC-1α and Nrf2, respectively. Moreover, the analysis of gut microbiota suggested that PSB\'s beneficial effects were partly due to its positive modulation of gut microbial composition and functionality. The findings of this study suggest the potential of dietary PSB as a candidate to improve hepatic lipid metabolism via several mechanisms. It may be developed as a treatment adjuvant in the future.
摘要：
肝脏脂质代谢受昼夜节律调节；因此，昼夜节律中断可能促进肥胖和肝脏脂质积累。本研究旨在探讨饮食中的蝶芪（PSB）对高脂饮食（HFD）诱导的脂质积累的保护作用，以及肠道菌群在其中的潜在作用。用HFD和慢性时差反应治疗小鼠14周。实验组在其饮食中补充0.25%(w/w)PSB以评估PSB是否具有有益效果。我们的研究发现，慢性时差加重HFD诱导的肥胖和肝脏脂质积累，但补充PSB可显著缓解这些不良反应.具体来说,PSB通过上调SIRT1表达促进肝脏脂解和β-氧化，间接减少脂质积累引起的氧化应激。此外,PSB诱导的SIRT1和SIRT3表达升高通过激活Nrf2介导的抗氧化酶帮助防止过度自噬和线粒体裂变。通过在体外研究中使用SIRT1和SIRT3抑制剂，这表明PSB对SIRT1和SIRT3的激活分别对PGC-1α和Nrf2的易位至关重要。此外，对肠道微生物群的分析表明，PSB的有益作用部分是由于其对肠道微生物组成和功能的积极调节。这项研究的结果表明，膳食PSB可能通过多种机制改善肝脂质代谢。它将来可能会被开发为治疗佐剂。
