Elevated Drp1-mediated mitochondrial fission was proposed to promote NAFLD, as inhibition of hepatic Drp1 in early life prevented high-fat diet induced liver steatosis in mice. However, whether Drp1-knockdown (Drp1si) can reverse established NASH in adulthood is unknown. Hepatocyte-restricted delivery of siRNA conjugated to N-acetyl-galactosamine (GalNac) is a safe and FDA-approved approach to selectively manipulate hepatic gene expression and treat human liver disease. Here, we show that hepatic Drp1si in adult healthy mice decreased body weight by 12% and induced liver damage, as shown by the elevation in circulating transaminases, liver inflammation, fibrosis and necrosis (p<0.001) . Decreased body weight was largely explained by Gdf15 actions decreasing food intake by 11%, as Gdf15 receptor (Gfral) KO prevented the decrease in food intake and mitigated the weight loss caused by Drp1-KD. An activation of the Atf4- integrated stress response (ISR) in liver explained the 4x fold increase in hepatic Gdf15 expression. Drp1si increased both ER stress and the activity of the mitochondrial protease Oma1, two processes that converge in increasing EIf2alpha phosphorylation and Atf4 expression. While NASH induced by GAN diet did not activate Oma1 by itself, Drp1si in mice with NASH was sufficient to activate Oma1 and exacerbate NASH-induced ER-stress. These led to higher ISR activation, exacerbated inflammation, fibrosis and necrosis.
In conclusion, our study supports that increased Drp1 activity is an adaptative mechanism counteracting NASH that prevents ISR overactivation and mitigates ER stress to limit fibrosis, inflammation, and necrosis. Our study argues against blocking Drp1 in hepatocytes to combat NASH.
J. Steffen: Employee; Janssen Research & Development, LLC. J. Ngo: None. S. Wang: None. H. F. Kramer: Employee; Janssen Research & Development, LLC. L. D. Norquay: Employee; Janssen Pharmaceuticals, Inc. A. Pocai: Employee; Johnson & Johnson. O. Shirihai: None. M. Liesa: None.