Iron metabolism mediates the relationship between Vitamin C and hepatic steatosis and fibrosis in NAFLD

Zhengyu Hu; Yan Li; Bingwei Ma; Saifei Lei; Xingchun Wang

doi:10.3389/fnut.2022.952056

Iron metabolism mediates the relationship between Vitamin C and hepatic steatosis and fibrosis in NAFLD

Front Nutr. 2022 Sep 8:9:952056. doi: 10.3389/fnut.2022.952056. eCollection 2022.

Authors

Zhengyu Hu¹, Yan Li², Bingwei Ma¹, Saifei Lei³, Xingchun Wang⁴

Affiliations

¹ Department of General Surgery, Shanghai Tenth People's Hospital, Affiliated to Tongji University School of Medicine, Shanghai, China.
² Department of Gastroenterology, Shanghai Tenth People's Hospital, Affiliated to Tongji University School of Medicine, Shanghai, China.
³ Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, United States.
⁴ Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China.

Abstract

Vitamin C (Vit C) and iron metabolism are closely related to metabolic disorders. However, the relation between iron storage protein ferritin and Vit C has not been elucidated. We aimed to investigate the crosstalk between Vit C and ferritin and its implications on non-alcoholic fatty liver disease (NAFLD). Clinical information of 3,614 subjects was obtained from the NHANES Public Data 2017-2018. FibroScan data, which estimates liver steatosis and fibrosis and Vit C, were selected to assess factors influencing NAFLD in this cross-sectional study. Ferritin and Vit C among different categories of liver steatosis and fibrosis were assessed by CAP and E value. Logistic regression and RCS models were used to analyze the correlations. In vitro study in hepG2 were conducted to validate the regulations. Ferritin increased while Vit C decreased with more severe hepatic steatosis and hepatic fibrosis (all P < 0.001). Logistic regression models indicated that increased serum ferritin was a risk factor for NAFLD while increased Vit C was a protective factor for NAFLD and hepatic fibrosis after adjusting the continuous and categorical variables. Vitamin C was negatively associated with ferritin. Further mediation analysis identified that ferritin mediates the impact of Vit C on NAFLD (P < 0.05) and cirrhosis (P < 0.001). The experiments on cellular level suggested Vit C alleviated PA/OA induced steatosis and maintains iron homeostasis through inhibiting PA/OA induced upregulation of iron bound protein ferritin and labile iron pool (LIP) induction in hepG2 cells. In conclusion, Vit C was a protective factor, whereas ferritin was a risk factor for hepatic steatosis and fibrosis. Vitamin C alleviated NAFLD and maintained iron homeostasis via ferritin suppression and LIP induction.

Keywords: NAFLD; Vitamin C; ferritin; hepatic fibrosis; hepatic steatosis.