Western diet promotes the progression of metabolic dysfunction‐associated steatotic liver disease in association with ferroptosis in male mice

• Published in: Physiological reports 2024-11, Vol.12 (23), p.e70139-n/a
• Main Authors: Maddie, Nicole, Chacko, Nefia, Matatov, David, Carrillo‐Sepulveda, Maria Alicia
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Body mass index; Carbohydrates; Cell death; Coenzyme A Ligases - metabolism; Diet; Diet, Western - adverse effects; Disease Progression; Drug therapy; Fatty liver; Ferroptosis; Glucose; Glutathione peroxidase; GPX4; Insulin resistance; Iron; Laboratory animals; Lipid Peroxidation; Lipids; Liver - metabolism; Liver - pathology; Liver diseases; Male; MASH; MASLD; Medical research; Metabolism; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease - etiology; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; Obesity; Obesity - metabolism; Obesity - pathology; Oxidative Stress; Proteins; Western diet
• ISSN: 2051-817X; 2051-817X
• DOI: 10.14814/phy2.70139

Non‐alcoholic fatty liver disease (NAFLD), now referred to as metabolic dysfunction‐associated steatotic liver disease (MASLD), is a silent killer that often progresses to metabolic dysfunction‐associated steatohepatitis (MASH). To date, there are no pharmacological treatments for MASLD. While obesity is a major cause of the development and progression of MASLD, the underlying mechanisms remain unclear. We hypothesize that ferroptosis, a recently discovered nonapoptotic iron‐dependent form of cell death, is activated during the progression of MASLD and may be a potential target for treating MASLD. Using a murine model of Western diet‐induced obesity, C57BL/6J male mice were exposed to a long‐term (36 weeks) Western diet. Controls were maintained with a standard chow diet. Western diet‐induced obesity was confirmed by increased body mass index (BMI). Histopathological analysis demonstrated the progression of MASLD to MASH in the obese group, which was accompanied by significant hepatic iron deposition, oxidative damage, and lipid peroxidation. Hepatic ferroptosis was further confirmed by decreased protein expression of glutathione peroxidase 4 (GPX4) and increased acyl‐CoA synthetase long‐chain family member 4 (ACSL4), markers of ferroptosis. These findings suggest that ferroptosis is a potential mechanism involved in the pathogenesis of MASLD in male mice. The graphical figure illustrates that long‐term Western diet‐induced obesity which in turn leads to (1) iron accumulation and (2) increased expression of ACSL4 and decreased expression of GPX4, markers of ferroptosis, in the livers. These effects were followed by hepatic (3) oxidative damage and (4) lipid peroxidation, events well‐known to lead to (5) ferroptosis and ultimately to (6) MASH.