Pancreastatin induces hepatic steatosis in type 2 diabetes by impeding mitochondrial functioning

Mitochondrial dysfunction is among the key factors for the advancement of hepatic steatosis to NAFLD and NASH. Pancreastatin (PST: human ChgA250-301) is a dysglycemic hormone, previously reported to promote steatosis and inflammation in various animal models of metabolic disorders. Recently, we observed PST deregulates energy expenditure and mitochondrial functioning in perimenopausal rats. In the current study, we aimed to decipher the role of PST instigated altered mitochondrial functioning in hepatic steatosis.

The HepG2 cells were PST exposed and the Chga gene was knocked down using siRNA and lipofectamine. Parallelly, type 2 diabetes (T2D) was developed in C57BL/6 mice by HFD feeding and administered PST inhibitor (PSTi8).

The PST exposed cells and HFD fed mice depicted: enhanced CHGA expression detected by IF/IHC, WB, and ELISA; dysregulated cellular ROS, mitochondrial ROS, oxygen consumption rate, mitochondrial membrane potential, ATP level, and NADP/NADP ratio; enhanced apoptosis determined by MTT, TUNEL, Annexin-V FITC, and WB of Bax/bcl2 and caspase 3; hepatic lipid accumulation upon Nile Red, Oil Red O, H&E staining, and the expression of SREBP-1c, FAS, ACC, and SCD; inflammation based on expression and circulatory level of IL6, IL-1β, and TNF-α. However, Chga knocked down HepG2 cells and PSTi8 treated mice unveiled protection from all the above abnormalities.

Collectively, the aforementioned data suggested the alteration in mitochondrial function induced by PST is responsible for hepatic steatosis in T2D.