Phloretic Acid Improves Metabolic Dysfunction-Associated Steatotic Liver Disease in High-Fat Diet-Fed Mice

Previous studies have demonstrated that phloretic acid (PA), a phenolic compound, exerts beneficial effects on inflammation, oxidative stress, and aging. However, its effects on obesity and associated metabolic abnormalities, including dyslipidemia and metabolic dysfunction-associated steatotic liver disease (MASLD), remain unclear. To evaluate the effects of PA on these obesity-related metabolic alterations and explore the underlying mechanisms, male C57BL/6J mice were divided into three groups and fed for 10 weeks with a low-fat diet (10 kcal% fat), a high-fat diet (HFD, 60 kcal% fat), or an HFD containing 0.02% (w/w) PA. PA-supplemented mice showed no significant weight loss and fat loss. However, PA supplementation significantly reduced circulating levels of free fatty acid, triglyceride, and non-high-density lipoprotein cholesterol (HDL-C) while increasing HDL-C levels in HFD-fed mice. It also reduced hepatic lipid deposition and alleviated hepatocellular injury. These effects were accompanied by the coordinated modulation of hepatic lipid metabolism, including reduced lipogenesis and cholesterol esterification, enhanced fatty acid oxidation, and increased bile acid synthesis and excretion. Furthermore, PA attenuated hepatic oxidative stress and suppressed systemic and hepatic inflammation. These observations suggest that PA may counteract HFD-induced MASLD by modulating hepatic lipid metabolism, and that its anti-inflammatory and antioxidant effects may also contribute to these metabolic improvements.