Combined therapy with pioglitazone and FGF21 mRNA synergistically ameliorates metabolic disorders in NAFLD rats

BACKGROUND: Current study aims to investigate the ameliorative effect of pioglitazone (PIO) combined with mRNA encoding FGF21 (termed mFGF21) on the metabolic disorders in rats with nonalcoholic fatty liver disease (NAFLD) and its potential mechanism. METHODS: In vitro functional activity of FGF21 protein expressed by mFGF21 was evaluated in human adipose-derived stem cells (hASCs). The pharmacokinetic profiles of FGF21 protein expressed by mFGF21 were investigated in normal SD rats and NAFLD rats, respectively. RESULTS: As the results, it showed that the PIO could enhanced in vitro functional activity of FGF21 protein expressed from mFGF21 in hASCs. Not only that, mFGF21 turns the body into a processing plant for endogenous protein expression, which enhanced the pharmacokinetic profiles of FGF21 proteins. Combined treatment with PIO and mFGF21 significantly reduced body weight, fasting blood glucose levels, insulin levels and lipid metabolism in NAFLD rats compared with control or both two monotherapy groups. The results of H&E staining and Western blot revealed that combined treatment with PIO and mFGF21 significantly decreased hepatic fat accumulation in NAFLD rats by activating the SHP1/AMPK signaling pathway. CONCLUSIONS: Our finding collectively demonstrated that PIO and mFGF21 combination therapy could synergistically ameliorate metabolic disorders in NAFLD rats.