Abstract
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.
Highlights
The increased low-density lipoprotein cholesterol (LDL-cholesterol or LDL) levels in plasma is a pivotal risk factor for the initiation of cardiovascular disease, the leading cause of death in all countries [1]
forkhead box O3 (FoxO3a) protein can interact with the insulin response element (IRE), which is overlapped by hepatocyte nuclear 1a (HNF1a) binding motif in proprotein convertase subtilisin/kexin 9 (PCSK9) promoter, so FoxO3a blocks the binding of HNF-1a to the PCSK9 promoter, thereby resulting in inhibition of PCSK9 expression [9]
We investigated if ascorbic acid can affect LDL levels and the action is completed by regulating PCSK9 and LDL receptor (LDLR) expression
Summary
The increased low-density lipoprotein cholesterol (LDL-cholesterol or LDL) levels in plasma is a pivotal risk factor for the initiation of cardiovascular disease, the leading cause of death in all countries [1]. Our results above suggest that ascorbic acid deficiency increased PCSK9 expression, which can make a substantial contribution to increased LDL levels in Gulo2/2 mice. Serum ascorbic acid levels were negatively correlated to serum CHO and LDL levels (Fig. 6, L and M), suggesting the role of ascorbic acid in regulating PCSK9 expression and cholesterol metabolism in humans.
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