Obesity and it associated complications is increasing in prevalence worldwide, highlighting the need to find therapeutics to either reduce obesity or treat obesity related conditions. One such condition, non-alcoholic fatty liver disease (NAFLD) is characterised by hepatic lipid deposition (steatosis) and drives diseases such as insulin resistance and type 2 diabetes (T2D). Moreover, NAFLD can progress to non-alcoholic steatohepatitis (NASH), characterised by scarring and fibrosis. NAFLD is present in up to 80 percent of individuals with T2D, and up to 90 percent of individuals with obesity. Limited diagnostic, prognostic and therapeutic tools are currently available to treat NAFLD.
Recently, our lab engaged a systems genetics approach in mice to identify novel proteins and pathways important in regulating hepatic lipid abundance. Findings from this study identified the protein PSMD9 as a previously unrecognised lipid regulatory protein. We validated a causal role for PSMD9 by demonstrating that hepatic overexpression of PSMD9 leads to increased plasma and hepatic lipid accrual, whilst silencing of PSMD9 with anti-sense oligonucleotides (ASOs) prevented liver steatosis in a short term study where mice were fed a western diet for 4 weeks. In the current study, we used ASO technology to silence PSMD9 in C57BL/6J and DBA2/J mice that were fed an AMLN NASH diet (HFD+22% fructose+2% cholesterol) over a prolonged period (6 months). Four groups of mice were studied: normal chow, AMLN+saline, AMLN+Control-ASO and AMLN+PSMD9-ASO. We demonstrate that PSMD9-ASOs silence both hepatic and adipose PSMD9. PSMD9-ASO treatment did not induce significant toxicity, and positively impacted several metabolic readouts of obesity, NAFLD and whole body metabolism; including significant reductions in weight gain. Thus, although preliminary, these studies warrant further investigations into the therapeutic potential of PSMD9-ASOs as a treatment for obesity and NAFLD.