515 - Oxidized Mitochondrial DNA Induces Steatohepatitis through CGAS Signaling Pathway

markedly, which was associated with decreases of the mitochondrial biogenesis signaling molecules PGC-1a and mitochondrial transcription factor-A, indicating suppressed mitochondrial biogenesis.Mitochondrial dynamics involves mitochondrial biogenesis and quality control.Proteins that mediate mitochondrial fission (Fis1, Drp1) and fusion (Mfn2) all decreased after treatment for 2 months and longer.Mitochondrial stress leads to NLRP3 inflammasome activation.NLRP3 and caspase-1 expression and activation and IL-1 formation all increased at 2 weeks and continued to increase afterwards, accompanied by markedly increased leukocyte infiltration.Mitochondrial oxidative stress and suppressed mitochondrial biogenesis could stimulate fibrosis.Profibrotic TGF-b1, a-smooth muscle actin expression (marker of stellate cell activation) and collagen-I expression increased, and mild sinusoidal and perivenular fibrosis occurred at 6 months as indicated by Trichrome staining.In addition, macrovesicular steatosis, increased ALT release, mild necrosis, apoptosis, and overt ballooning degeneration also occurred.Conclusion: Hepatic mitochondrial depolarization increased, whereas mitochondrial homeostasis became disrupted/suppressed in mice fed a Western diet.Such mitochondrial stress/dysfunction plays an essential role the proinflammatory and fibrotic responses in NASH (NIDDK, NIAAA).