Ferroptosis is a form of regulated cell death that is caused by the iron-dependent peroxidation of lipids 1,2. The glutathione-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4) prevents ferroptosis by converting lipid hydroperoxides into non-toxic lipid alcohols 3,4. Ferroptosis has been implicated in the cell death that underlies several degenerative conditions 2 , and induction of ferroptosis by inhibition of GPX4 has emerged as a therapeutic strategy to trigger cancer cell death 5. However, sensitivity to GPX4 inhibitors varies greatly across cancer cell lines 6 , suggesting that additional factors govern resistance to ferroptosis. Here, employing a synthetic lethal CRISPR/Cas9 screen, we identify ferroptosis suppressor protein 1 (FSP1) (previously Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Diets high in saturated fat and fructose have been implicated in the development of obesity and nonalcoholic steatohepatitis (NASH) in humans. We hypothesized that mice exposed to a similar diet would develop NASH with fibrosis associated with increased hepatic oxidative stress that would be further reflected by increased plasma levels of the respiratory chain component, oxidized coenzyme Q9 ( ox CoQ9). Adult male C57Bl/6 mice were randomly assigned to chow, high-fat (HF), or high-fat high-carbohydrate (HFHC) diets for 16 weeks. The chow and HF mice had free access to pure water, whereas the HFHC group received water with 55% fructose and 45% sucrose (wt/vol). The HFHC and HF groups had increased body weight, body fat mass, fasting glucose, and were insulin-resistant compared with chow mice. HF and HFHC consumed similar calories. Hepatic triglyceride content, plasma alanine aminotransferase, and liver weight were significantly increased in HF and HFHC mice compared with chow mice. Plasma cholesterol (P < 0.001), histological hepatic fibrosis, liver hydroxyproline content (P 5 0.006), collagen 1 messenger RNA (P 5 0.003), CD11b-F4/801Gr11 monocytes (P < 0.0001), transforming growth factor b1 mRNA (P 5 0.04), and a-smooth muscle actin messenger RNA (P 5 0.001) levels were significantly increased in HFHC mice. Hepatic oxidative stress, as indicated by liver superoxide expression (P 5 0.002), 4-hydroxynonenal, and plasma ox CoQ9 (P < 0.001) levels, was highest in HFHC mice. Conclusion: These findings demonstrate that nongenetically modified mice maintained on an HFHC diet in addition to developing obesity have increased hepatic ROS and a NASH-like phenotype with significant fibrosis. Plasma ox CoQ9 correlated with fibrosis progression. The mechanism of fibrosis may involve fructose inducing increased ROS associated with CD11b1F4/801Gr11 hepatic macrophage aggregation, resulting in transforming growth factor b1-signaled collagen deposition and histologically visible hepatic fibrosis. (HEPATOLOGY 2010;52:934-944) Abbreviations: a-SMA, a-smooth muscle actin; ALT, alanine aminotransferase; ANOVA, analysis of variance; DHE, dihydroethidium; HFHC, high-fat, highcarbohydrate; HF, high-fat; HOMA-IR, homeostasis model assessment of insulin resistance; mRNA, messenger RNA; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; ox CoQ9, oxidized coenzyme Q9; PCR, polymerase chain reaction; red CoQ9, reduced coenzyme Q9; ROS, reactive oxygen species; RT-PCR, reverse-transcription PCR; TG, triglyceride; TGF-b1, transforming growth factor b1.From the

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