Effects of a PEGylated fibroblast growth factor 21 variant on steatosis, inflammation, and fibrosis in a mouse model of nonalcoholic steatohepatitis

Combined Therapy with a CCR2/CCR5 Antagonist and FGF21 Analogue Synergizes in Ameliorating Steatohepatitis and Fibrosis

“…On the other hand, effects on fibrosis improvement by CCR2/CCR5 inhibition have been reported before in the MCD diet model [ 17 ], to a similar extent as we describe it now for the CDAHFD. Additionally, the PEG-FGF21v as monotherapy has been demonstrated to show therapeutic benefit on parameters of weight loss, steatosis and fibrosis in the CDAHFD mouse [ 45 ]. However, the CDAHFD model lacks some features of the metabolic syndrome such as obesity or insulin resistance.…”

Evaluation of a PEGylated Fibroblast Growth Factor 21 Variant Using Novel Preclinical Magnetic Resonance Imaging and Magnetic Resonance Elastography in a Mouse Model of Nonalcoholic Steatohepatitis

“…The investigative procedures regarding diet and treatment groups were conducted in the same manner at both sites, as follows: 6‐week‐old, male C57BL/6J mice were purchased from Jackson Laboratories (Bar Harbor, ME) and acclimated to either the BMS (single‐housed, N = 36) or Mayo Clinic animal facilities (group‐housed, 3–4 per cage, N = 42) for 1 week on standard rodent chow (BMS: Teklad, 2018, Madison, WI; Mayo Clinic: Lab Diet 5053 PicoLab® Rodent Diet‐20; St. Louis, MO). At 7 weeks of age, mice of normal body weight (~22–24 g) were randomized to receive either a matched control diet (CD) containing standard levels of choline, methionine, and fat (Research Diets, A13012807, New Brunswick, NJ) or a choline‐deficient, amino acid‐defined, (methionine, 0.1%), high‐fat (60% of calories from fat) diet (CDAHFD; Research Diets, A06071302, New Brunswick, NJ) 10–12,33 …”

“…Native FGF21 administration in diabetic preclinical models improves glucose and lipid profiles 9 . Analogues of FGF21 have been shown to improve insulin sensitivity, lipid profiles, and reduce steatosis and fibrosis in preclinical and clinical studies 10–14 . Pegbelfermin, a polyethylene glycol‐conjugated (PEGylated) human FGF21 analogue, 15 has been shown to improve hepatic steatosis and biomarkers of hepatic injury and fibrosis in clinical trials 16,17 …”

“…There is potential translational value that may be gained by studying MRI hepatic fat fraction (MRI‐HFF) and MRE shear stiffness (MRE‐SS) paired with traditional histological assessment in a robust animal model of NASH, such as the choline‐deficient, amino acid‐defined, high‐fat diet (CDAHFD) mouse model. The CDAHFD mouse model is a rapidly progressive and robust model of NASH that has been used in the development of effective therapeutics to better understand the disease 12,33 . Thus, the aim of this study was to investigate if a PEGylated FGF21 variant (PEG‐FGF21v), administered twice weekly (BIW) for 8 weeks, improves metabolic and fibrotic parameters in the CDAHFD mouse model of NASH and to examine steatosis and fibrosis via novel noninvasive imaging means utilizing MRI‐HFF and MRE‐SS compared with conventional histological evaluation.…”

“…9 Analogues of FGF21 have been shown to improve insulin sensitivity, lipid profiles, and reduce steatosis and fibrosis in preclinical and clinical studies. [10][11][12][13][14] Pegbelfermin, a polyethylene glycol-conjugated (PEGylated) human FGF21 analogue, 15 has been shown to improve hepatic steatosis and biomarkers of hepatic injury and fibrosis in clinical trials. 16,17 Histological analysis of liver tissue collected via biopsy is currently the most accurate method of evaluating the steatosis, lobular inflammation, ballooning, and fibrosis characteristic of patients with NASH.…”