Vitamin D supplementation alleviates high fat diet-induced metabolic associated fatty liver disease by inhibiting ferroptosis pathway

Abstract

Purpose: Recently, a significant negative correlation has been found between vitamin D (VD) and metabolic associated fatty liver disease (MAFLD), suggesting a potential beneficial role of VD in preventing of MAFLD, while underscoring the importance of exploring its mechanisms.

Methods: The experiment comprised two parts: male C57BL/6J mice (6 weeks) were fed a high-fat diet (HFD) and intraperitoneally injected with vitamin D₃ (VD₃) (1.68 IU/g/week) for 16 weeks. Meanwhile, palmitic acid (PA)-induced HepG2 cells were treated with 1,25(OH)₂D₃ (10 nM). The general conditions of the mice were evaluated by measuring body weight, liver/body weight, serum biochemical parameters, and inflammation indices. Additionally, injury-associated indices and histopathology were used to assess the severity of liver injury. Furthermore, indicators of ferroptosis, including lipid peroxidation, iron aggregation, and the aberrant expression of related proteins, were determined using Prussian blue staining, ELISA assay, and Western blot.

Results: Long-term VD₃ administration significantly reduced body weight gain and the liver/body weight ratio of HFD-induced MAFLD mice, while also improving serum lipid metabolism dysregulation and enhancing insulin sensitivity. The changes in the expressions of liver injury indices and histological manifestations due to VD₃ treatment indicated that VD₃ may exerts beneficial effects on liver injury through inhibiting inflammatory cell infiltration and vacuolation. Importantly, VD₃ supplementation also inhibited ferroptosis by enhancing the body's antioxidant capacity, reducing local iron aggregation, and modulating the expression levels of ferroptosis-related proteins. These findings were further confirmed in a PA-induced HepG2 steatosis cell model, highlighting the pharmacological effects of VD.

Conclusions: VD shows promise in mitigating HFD -induced liver injury by improving metabolic dysregulation and inhibiting ferroptosis, suggesting therapeutic potential in MAFLD.

Keywords: Ferroptosis; High fatty diet; Metabolic associated fatty liver disease; Vitamin D.