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A collaborative study between Dr. Liesa’s laboratory and Janssen R&D demonstrates that decreasing Drp1-mediated mitochondrial fission, using an FDA approved delivery method of siRNA to hepatocytes, exacerbates non-alcoholic steatohepatitis in mice.

    The use of siRNA conjugated to N-acetyl-galactosamine (NAG-siRNA) is an approach approved by the FDA to treat human liver diseases by knocking down pathogenic genes. In this study, we determined whether decreasing the expression of the mitochondrial fission protein Drp1 could reverse liver disease in mice with established non-alcoholic steatohepatitis. We found that Drp1 is required to mitigate NASH severity and thus argues against blocking Drp1 in hepatocytes to combat NASH.

    Abstract

    The mitochondrial fission protein Drp1 was proposed to promote non-alcoholic fatty liver disease, as inhibition of hepatocyte Drp1 early in life prevents liver steatosis induced by high-fat diet in mice. However, whether Drp1-knockdown in older mice can reverse established non-alcoholic steatohepatitis (NASH) is unknown. N-acetylgalactosamine-siRNA conjugates, an FDA approved method to deliver siRNA selectively to hepatocytes, were used to knockdown hepatocyte-Drp1 in mice (NAG-Drp1si). NAG-Drp1si treatment decreased body weight and induced liver inflammation in adult healthy mice. Increased hepatic Gdf15 production was the major contributor to body-weight loss caused by NAG-Drp1si treatment, as Gdf15 receptor deletion (Gfral KO) prevented the decrease in food intake and mitigated weight loss. NAG-Drp1si activated the Atf4-controlled integrated stress response (ISR) to increase hepatic Gdf15 expression. NAG-Drp1si in healthy mice caused ER stress and activated the mitochondrial protease Oma1, which are the ER and mitochondrial triggers that activate the Atf4-controlled ISR. Drp1 mitigates NASH by decreasing ER stress, preventing Oma1 activation and ISR exacerbation. The elevation in Gdf15 actions induced by NAG-Drp1si might represent an adaptive response decreasing the nutrient load to liver when mitochondria are misfunctional. Our study argues against blocking Drp1 in hepatocytes to combat NASH.

    Reference:

    Ngo et al. The mitochondrial fission protein Drp1 in liver is required to mitigate NASH and prevents the activation of the mitochondrial ISR. Molecular Metabolism, 2022; 64:101566. doi: 10.1016/j.molmet.2022.101566

    Mitochondria in hepatocytes from mice with NASH (GAN diet) and treated with NAG-Drp1si
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