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  3. Ascorbic acid enhances low-density lipoprotein receptor expression by suppressing proprotein convertase subtilisin/kexin 9 expression

Ascorbic acid enhances low-density lipoprotein receptor expression by suppressing proprotein convertase subtilisin/kexin 9 expression

  • J Biol Chem. 2020 Nov 20;295(47):15870-15882. doi: 10.1074/jbc.RA120.015623.
Dandan Wang 1,  Xiaoxiao Yang 1,  Yuanli Chen 1,  Ke Gong 1,  Maoyun Yu 2,  Yongyao Gao 1,  Ximei Wu 3,  Huaqing Hu 4,  Chenzhong Liao 1,  Jihong Han 5,  Yajun Duan 6
Affiliations

Affiliations

  • 1 Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, School of Food and Biological Engineering, Hefei University of Technology, Hefei, China.
  • 2 School of Biological and Pharmaceutical Engineering, West Anhui University, Lu'An, China.
  • 3 School of Medicine, Zhejiang University, Hangzhou, China.
  • 4 First Affiliated Hospital of Anhui Medical University, Hefei, China.
  • 5 Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, School of Food and Biological Engineering, Hefei University of Technology, Hefei, China; College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China. Electronic address: jihonghan2008@nankai.edu.cn.
  • 6 Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, School of Food and Biological Engineering, Hefei University of Technology, Hefei, China. Electronic address: yduan@hfut.edu.cn.
PMID: 32913121 DOI: 10.1074/jbc.RA120.015623
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.

Keywords

FoxO3a; LDL; LDLR; PCSK9; ascorbic acid; forkhead box P3 (FOXP3).; lipoprotein metabolism; lipoprotein receptor; low-density lipoprotein); proprotein convertase subtilisin/kexin type 9.

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