The activity of proteinase is reported to correlate with the development and progression of nonalcoholic fatty liver disease (NAFLD). Puromycin-sensitive aminopeptidase (PSA/NPEPPS) is an integral nontransmembrane enzyme that functions to catalyze the cleavage of amino acids near the N-terminus of polypeptides. A previous study suggested that this enzyme acts as a regulator of neuropeptide activity; however, the metabolic function of this enzyme in the liver has not been explored. Here, we identified the novel role of PSA in hepatic lipid metabolism. Specifically, PSA expression was lower in fatty livers from NAFLD patients and mice (HFD, ob/ob, and db/db). PSA knockdown in cultured hepatocytes exacerbated diet-induced triglyceride accumulation through enhanced lipogenesis and attenuated fatty acid β-oxidation. Moreover, PSA mediated activation of the master regulator of antioxidant response, nuclear factor erythroid 2-related factor 2 (NRF2), by stabilizing NRF2 protein expression, which further induced downstream antioxidant enzymes to protect the liver from oxidative stress and lipid overload. Accordingly, liver-specific PSA overexpression attenuated hepatic lipid accumulation and steatosis in ob/ob mice. Furthermore, in human liver tissue samples, decreased PSA expression correlated with the progression of NAFLD. Overall, our findings suggest that PSA is a pivotal regulator of hepatic lipid metabolism and its antioxidant function occurs by suppressing NRF2 ubiquitination. Moreover, PSA may be a potential biomarker and therapeutic target for treating NAFLD.

中文翻译：

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PSA通过调节NRF2信号通路控制肝脏脂质代谢

据报道，蛋白酶的活性与非酒精性脂肪肝疾病 (NAFLD) 的发展和进展相关。嘌呤霉素敏感氨肽酶 (PSA/NPEPPS) 是一种完整的非跨膜酶，其功能是催化多肽 N 末端附近氨基酸的切割。先前的一项研究表明，这种酶可作为神经肽活性的调节剂。然而，尚未探索这种酶在肝脏中的代谢功能。在这里，我们确定了 PSA 在肝脏脂质代谢中的新作用。具体而言，NAFLD 患者和小鼠（HFD、 ob/ob和db/db）的脂肪肝中 PSA 表达较低）。培养的肝细胞中的 PSA 敲低通过增强脂肪生成和减弱脂肪酸β-氧化加剧了饮食诱导的甘油三酯积累。此外，PSA通过稳定NRF2蛋白表达介导抗氧化反应的主要调节因子——核因子红细胞2相关因子2（NRF2）的激活，进一步诱导下游抗氧化酶保护肝脏免受氧化应激和脂质过载。因此，肝脏特异性 PSA 过表达减弱了ob/ob中的肝脏脂质积累和脂肪变性老鼠。此外，在人类肝组织样本中，PSA 表达降低与 NAFLD 的进展相关。总体而言，我们的研究结果表明，PSA 是肝脏脂质代谢的关键调节剂，其抗氧化功能通过抑制 NRF2 泛素化而发生。此外，PSA可能是治疗NAFLD的潜在生物标志物和治疗靶点。