Oral Presentation ANZOS Annual Scientific Meeting 2021

The contribution of PSMD9 to the regulation of hepatic lipid metabolism (#40)

Michael F Keating 1 , Simon T Bond 1 , Christine Yang 1 , Yingying Liu 1 , Tim Sikora 1 , Adele L Richart 1 , Aaron W Jurrjens 1 , Peter J Meikle 1 , Brian G Drew 1 , Anna C Calkin 1
  1. Baker Heart and Diabetes Institute, Melbourne, VICTORIA, Australia

Perturbations to lipid homeostasis can promote deleterious metabolic pathologies including hepatic lipotoxicity and insulin resistance. Indeed, non-alcoholic fatty liver disease (NAFLD) is associated with both obesity and type 2 diabetes. Here, we characterise the protein, 26S proteasome non-ATPase regulatory subunit 9 (PSMD9), in the setting of excess lipid consumption which drives lipotoxicity and metabolic dysregulation.

To assess the in vivo contribution of PSMD9 to lipid metabolism, C57BL/6J and DBA/2J mice were administered an anti-sense oligonucleotide (ASO) against PSMD9 to silence expression while concomitantly being administered a Western Diet for 4 weeks. PSMD9-ASO treatment was associated with robust knockdown of PSMD9 in both liver and white adipose tissue (WAT), as well as reduced weight gain compared to control ASO mice. Moreover, PSMD9-ASO treated mice exhibited significant reductions in the expression of key genes and proteins of the de novo lipogenesis (DNL) pathway, in both the liver and WAT. Furthermore, PSMD9-ASO treated mice exhibited significantly reduced hepatic and WAT triacylglycerol and diacylglycerol accumulation as well as reductions in plasma glucose levels.

Likewise, PSMD9-ASO mice fed a high fat, high fructose diet for 26 weeks exhibited significant reductions in weight gain and markers of DNL, in epididymal and subcutaneous WAT, with increased expression of browning genes in subcutaneous WAT compared to control ASO mice. Moreover, to delineate the metabolic effect of PSMD9 ablation in a tissue-specific manner, we generated a liver-specific PSMD9 knockout (KO) mouse. PSMD9 KO mice fed a HFD for 16 weeks exhibited increased liver mass with a converse reduction in epididymal WAT. Moreover, hepatic expression of genes from the DNL pathway were modulated in PSMD9 KO mice.

In summary, these studies suggest that PSMD9 may be an attractive target for therapeutic attenuation of hepatic lipid accrual associated with NAFLD.