Neutralization of Oxidized Phospholipids Ameliorates Non-alcoholic Steatohepatitis

Abstract

Highlights d Oxidized phospholipids (OxPLs) accumulate in non-alcoholic steatohepatitis (NASH) d OxPLs induce oxidative stress and mitochondrial damage, in part by modifying MnSOD d Neutralizing OxPLs improved mitochondrial function and biogenesis in NASH d Neutralizing OxPLs ameliorates NASH Authors

Oxidized Lipids and CD36-Mediated Lipid Peroxidation in CD8 T Cells Suppress Anti-Tumor Immune Responses

“…LDL-bound PUFAs are prone to ROS-mediated lipid peroxidation . It has been shown that OxLDL or OxPLs cause oxidative stress, inhibit mitochondrial activity, and induce lipid peroxidation in primary hepatocytes (Sun et al, 2020). However, OxLDL per se is likely not the only source of oxidized lipids because as the E06 staining noted, OxPLs were highly abundant in the TME and dying tumor cell vesicles and apoptotic bodies could be other sources of CD36-mediated uptake of oxidized lipids.…”

“…OxLDL and OxPLs induce oxidative stress in macrophages and endothelial cells, and promote lipid peroxidation in non-alcoholic fatty liver disease (Navab et al, 2004;Que et al, 2018;Sun et al, 2020;Witztum and Steinberg, 1991). Because we found that CD8 + TILs take up OxLDL in a CD36-dependent manner (Fig 4B), we hypothesized that this would increase lipid peroxidation.…”

Dual targeting of hepatic fibrosis and atherogenesis by icosabutate, an engineered eicosapentaenoic acid derivative

“…42 However, icosabutate was able to markedly decrease both hepatic GSSG and hepatic oxPLs in AMLN ob/ob mice, an effect that likely benefits from the fact that α-substituted EPA avoids incorporation into phospholipids. 41 The decrease in PC-AA in response to icosabutate may also contribute to the Interestingly, in AMLN diet-induced NASH in Ldlr −/− mice, it has recently been shown that neutralisation of oxPLs substantially reduces hepatic apoptosis, 43 a crucial driver of liver injury in NASH. 44 This corresponds well with our findings in AMLN ob/ob mice, with a decrease in oxPLs occurring in conjunction with a significant reduction in apoptosis in response to icosabutate treatment.…”

The Nuclear Envelope in Lipid Metabolism and Pathogenesis of NAFLD

“…Indeed, a recent report demonstrates that oxidized phospholipids accumulate in human and mouse NASH. Moreover, administration of an antibody that neutralizes the oxidized lipid species improves features of NASH in rodent models [ 9 ].…”

“…The lack of an effective treatment for NASH is due in part to the incomplete understanding of the pathogenesis of NAFLD and NASH, which is hampered by the complexity of the disorders. Growing evidence suggests that NASH is a multifaceted process that requires the convergence of diverse genetic, metabolic, and environmental factors [ 5 , 6 , 7 , 8 , 9 ]. Numerous pharmaceutical and biotechnology companies are devoting significant efforts to better understand NASH and develop treatments.…”