Ascorbic acid, a water-soluble antioxidant, regulates various biological processes and is thought to influence cholesterol. However, little is known about the mechanisms underpinning ascorbic acid-mediated cholesterol metabolism. Here, we determined if ascorbic acid can regulate expression of proprotein convertase subtilisin/kexin 9 (PCSK9), which binds low-density lipoprotein receptor (LDLR) leading to its intracellular degradation, to influence low-density lipoprotein (LDL) metabolism. At cellular levels, ascorbic acid inhibited PCSK9 expression in HepG2 and Huh7 cell lines. Consequently, LDLR expression and cellular LDL uptake were enhanced. Similar effects of ascorbic acid on PCSK9 and LDLR expression were observed in mouse primary hepatocytes. Mechanistically, ascorbic acid suppressed PCSK9 expression in a forkhead box O3-dependent manner. In addition, ascorbic acid increased LDLR transcription by regulating sterol regulatory element-binding protein 2. In vivo, administration of ascorbic acid reduced serum PCSK9 levels and enhanced liver LDLR expression in C57BL/6J mice. Reciprocally, lack of ascorbic acid supplementation in L-gulono-γ-lactone oxidase deficient (Gulo−/−) mice increased circulating PCSK9 and LDL levels, and decreased liver LDLR expression, whereas ascorbic acid supplementation decreased PCSK9 and increased LDLR expression, ameliorating LDL levels in Gulo−/− mice fed a high fat diet. Moreover, ascorbic acid levels were negatively correlated to PCSK9, total and LDL levels in human serum samples. Taken together, these findings suggest that ascorbic acid reduces PCSK9 expression, leading to increased LDLR expression and cellular LDL uptake. Thus, supplementation of ascorbic acid may ameliorate lipid profiles in ascorbic acid-deficient species.

中文翻译：

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抗坏血酸通过抑制前蛋白转化酶枯草杆菌蛋白酶/kexin 9 表达来增强低密度脂蛋白受体表达。

抗坏血酸是一种水溶性抗氧化剂，可调节各种生物过程并被认为会影响胆固醇。然而，关于支持抗坏血酸介导的胆固醇代谢的机制知之甚少。在这里，我们确定抗坏血酸是否可以调节前蛋白转化酶枯草杆菌蛋白酶/kexin 9 (PCSK9) 的表达，PCSK9 结合低密度脂蛋白受体 (LDLR) 导致其细胞内降解，从而影响低密度脂蛋白 (LDL) 代谢。在细胞水平上，抗坏血酸抑制了 HepG2 和 Huh7 细胞系中 PCSK9 的表达。因此，LDLR 表达和细胞 LDL 摄取得到增强。在小鼠原代肝细胞中观察到抗坏血酸对 PCSK9 和 LDLR 表达的类似影响。从机制上讲，抗坏血酸以叉头盒 O3 依赖性方式抑制 PCSK9 表达。此外，抗坏血酸通过调节甾醇调节元件结合蛋白 2 来增加 LDLR 转录。在体内，抗坏血酸的给药降低了 C57BL/6J 小鼠的血清 PCSK9 水平并增强了肝脏 LDLR 表达。相反，L-古洛糖酸-γ-内酯氧化酶缺陷（Gulo-/-）小鼠缺乏抗坏血酸补充剂会增加循环 PCSK9 和 LDL 水平，并降低肝脏 LDLR 表达，而补充抗坏血酸会降低 PCSK9 和增加 LDLR 表达，从而改善 LDL喂食高脂肪饮食的 Gulo-/- 小鼠中的水平。此外，抗坏血酸水平与人血清样品中的 PCSK9、总和 LDL 水平呈负相关。总之，这些发现表明抗坏血酸降低 PCSK9 表达，导致 LDLR 表达和细胞 LDL 摄取增加。因此，