Ascorbic acid enhances low-density lipoprotein receptor expression by suppressing proprotein convertase...

Area of Science:

• Biochemistry
• Molecular Biology
• Nutritional Science

Background:

• Ascorbic acid (vitamin C) is a vital antioxidant with poorly understood roles in cholesterol metabolism.
• Proprotein convertase subtilisin/kexin 9 (PCSK9) is a key regulator of low-density lipoprotein (LDL) receptor (LDLR) levels and LDL metabolism.
• The precise mechanisms by which ascorbic acid influences cholesterol regulation remain largely undefined.

Purpose of the Study:

• To investigate whether ascorbic acid modulates PCSK9 expression to affect LDL metabolism.
• To elucidate the molecular pathways involved in ascorbic acid's regulation of cholesterol homeostasis.
• To assess the therapeutic potential of ascorbic acid in managing lipid profiles.

Main Methods:

• Cellular assays using HepG2 and Huh7 cell lines to examine ascorbic acid's effect on PCSK9 and LDLR expression.
• Primary mouse hepatocytes and *in vivo* studies in C57BL/6J and *Gulo*^-/- mice.
• Analysis of gene expression, protein levels, LDL uptake, and serum lipid profiles.
• Investigation of mechanistic pathways involving forkhead box O3 (FOXO3) and sterol regulatory element-binding protein 2 (SREBP2).

Main Results:

• Ascorbic acid significantly inhibited PCSK9 expression and enhanced LDLR expression and LDL uptake in vitro and in vivo.
• Mechanistically, ascorbic acid suppressed PCSK9 via FOXO3 and increased LDLR transcription through SREBP2.
• Ascorbic acid supplementation ameliorated high LDL levels in ascorbic acid-deficient mice, while deficiency exacerbated them.
• Human serum samples showed a negative correlation between ascorbic acid levels and PCSK9, total cholesterol, and LDL levels.

Conclusions:

• Ascorbic acid reduces PCSK9 expression, thereby increasing LDLR expression and enhancing cellular LDL clearance.
• These findings establish a novel mechanism for ascorbic acid in cholesterol metabolism.
• Ascorbic acid supplementation may represent a viable strategy to improve lipid profiles, particularly in ascorbic acid-deficient individuals.