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

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.

Examining the Pathogenesis of MAFLD and the Medicinal Properties of Natural Products from a Metabolic Perspective

“…Vitamin C and vitamin E, also known as ascorbic acid and tocopherol, respectively, play significant roles in the redox system because of their excellent antioxidant activity. Abundant epidemiologic evidence has demonstrated that a high vitamin C intake level is a protective factor for MAFLD [182][183][184]. Vitamin C deficiency increases hepatic steatosis, oxidative stress, fibrosis, and inflammation, which is an important potential pathogenic factor of MAFLD [185].…”

“…However, there is also evidence that chronic vitamin C deficiency impairs SREBP1c activation, thereby inhibiting hepatic de novo lipogenesis and suppressing MAFLD progression [190]. Notably, vitamin C also plays an important role in maintaining iron homeostasis and is strongly associated with MAFLD [184]. This reflects the crosstalk between vitamins and minerals.…”

Systematic analysis of the relationship between non-alcoholic fatty liver disease and tissue iron overload: promising areas for the use of polypeptide therapy

“…Повышенный ферритин сыворотки был фактором риска НАЖБП, а повышенный уровень витамина С, напротив, был защитным фактором от НАЖБП и фиброза печени. Эксперименты на гепатоцитах линии hepG2 показали, что витамин C облегчает стеатоз и поддерживает гомеостаз железа за счет ингибирования повышения ферритина и пула лабильного железа [18]. Концентрации железа в сыворотке крови были обратно пропорциональны риску НАЖБП при прогрессирующем фиброзе печени (P = 0.018) [19].…”

Mitochondrial Dysfunction in Metabolic Dysfunction Fatty Liver Disease (MAFLD)

“…To maintain the balance of the mitochondrial oxidation reaction, mitochondria have antioxidation enzymes and antioxidant molecules (glutathione, VE, etc.) to eliminate mt-ROS accumulation by capturing and removing free radicals and harmful substances to repair oxidative damage [83]. Recently, it has been found that the nuclear factor-κB (NF-κB) pathway has bidirectional effects in different stages of the oxidative stress response in the pathogenesis of MAFLD [84].…”

“…According to its antioxidant properties, VC plays an important role in scavenging oxygen free radicals. The basic mechanism by which VC alleviates the degree of oxidative stress is through reducing the generation of mt-ROS and increasing the levels of antioxidant enzymes such as superoxide dismutase and GSH peroxidase, thereby improving the activity of the ETC [83]. At the same time, VC inhibits fat accumulation by activating PPARα in MAFLD.…”