A New Synthetic Analogue of Protectin DX With Enhanced Therapeutic Potential Against Metabolic-Associated Steatotic Liver Disease

Abstract

Obesity, characterized by chronic low-grade inflammation, promotes numerous complications such as type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD). A class of lipid mediators known as specialized pro-resolving mediators (SPMs) has garnered interest in this field due to their capacity to promote the resolution of inflammation. One such SPM is Protectin DX (PDX), the stereoisomer of Protectin D1 (PD1). We previously reported that PDX treatment protects against lipid-induced and obesity-linked insulin resistance and attenuates end-stage renal failure in T2D animal models. Our group recently developed a cost-efficient synthesis of PDX and structural analogues to accelerate research on PDX functions and to scale up the production of these molecules to facilitate their pharmaceutical development. After synthesizing and screening over 30 PDX analogues for their bioactivity in relevant cellular models, two analogues, AN-44 and AN-48, were selected for their ability to reduce macrophage inflammation and stimulate muscle glucose uptake in vitro. Since AN-48 also lowers plasma TNF-α in a hamster model of metabolic endotoxemia, it was selected for longer-term in vivo studies. AN-48 (50 ng/g) administered orally daily was found to fully prevent hepatic triglyceride accretion in diet-induced obese hamsters. AN-48 also prevented fasting hyperinsulinemia, insulin resistance, and reduced hepatic inflammation as compared to vehicle or PDX treatments. These results identify AN-48 as a cost-efficient and novel PDX analogue with high therapeutic potential against obesity-linked T2D and MASLD.

Keywords: MASLD; inflammation resolution; insulin resistance; triglycerides; type 2 diabetes.