Therapeutic evaluation of the novel FGF21 analogue DC2303 for metabolic dysfunction-associated steatohepatitis

Abstract Metabolic dysfunction-associated steatohepatitis (MASH) is a liver pathological manifestation of the metabolic syndrome, affecting about 25% of the world 's population. As the number of obese patients increases, this number continues to rise. Fibroblast growth factor 21 (FGF21), an endogenous hormone that regulates energy homeostasis and glucolipid metabolism, has recently emerged as a promising candidate target for the treatment of metabolic diseases. In order to solve the limitations of FGF21, such as short half-life and poor stability in vivo. We synthesized a new long-acting FGF21 analogue DC2303 by conjugating PASylated FGF21 with a variety of functional side chains modified by fatty acids to achieve dimerization. The aim of this study was to evaluate the therapeutic effect of DC2303 on MASH and to elucidate its mechanism of action. MASH model was established by inducing db/db mice with 60% High fat diet (HFD), serum Triglyceride (TG), Insulin and Interleukin-17A (IL-17A) were measured by ELISA, histopathological analysis of the livers of MASH mice was performed by HE staining and Oil red O staining, and the lipids in the livers of MASH mice were detected by Western blotting and Quantitative real-time PCR (RT-PCR) related protein and mRNA expression levels in the liver of MASH mice. The results showed that DC2303 could not only reduce body weight, blood glucose and blood lipid levels in a dose-dependent manner, but also reduce inflammation and improve insulin resistance. It also reduced the expression levels of CD36 and Stearoyl-CoA desaturase 1 (SCD-1) and increased the expression levels of Peroxisome proliferator-activated receptor alpha (PPARα) and Carnitine palmitoyltransferase-1alpha (CPT-1α) in the liver, thereby inhibiting hepatic lipid accumulation and reversing hepatic steatosis. This study demonstrates for the first time that DC2303, a novel long-acting FGF21 analogue, may be a potential candidate drug to improve the multiple physiological and pathological mechanisms of MASH.