Targeting ferroptosis alleviates methionine‐choline deficient (MCD)‐diet induced NASH by suppressing liver lipotoxicity

Li, Xiaoya; Wang, Tianxiang; Huang, Xinmei; Li, Yue; Sun, Tiange; Zang, Shufei; Guan, Kun‐Liang; Xiong, Yue; Li, Jun; Yuan, Hai‐Xin

doi:10.1111/liv.14428

Cited by 147 publications

(122 citation statements)

References 54 publications

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“…Ferroptosis is also implicated in nonalcoholic steatohepatitis induced by a choline-deficient and ethionine-supplemented diet or methionine-choline-deficient diet. 185 Conversely, induced ferroptosis may be beneficial in the treatment of certain liver diseases, such as liver fibrosis or parasite infections of Plasmodium at the liver stage. 72,186 The heterozygous knockout of GPX4 in intestinal epithelial cells increases the inflammatory bowel disease (IBD) in mice caused by a PUFA-rich Western diet (containing 10% fish oil with omega-3 and omega-6 PUFAs).…”

Section: Digestive Systemmentioning

confidence: 99%

Ferroptosis: molecular mechanisms and health implications

et al. 2020

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Cell death can be executed through different subroutines. Since the description of ferroptosis as an iron-dependent form of non-apoptotic cell death in 2012, there has been mounting interest in the process and function of ferroptosis. Ferroptosis can occur through two major pathways, the extrinsic or transporter-dependent pathway and the intrinsic or enzyme-regulated pathway. Ferroptosis is caused by a redox imbalance between the production of oxidants and antioxidants, which is driven by the abnormal expression and activity of multiple redox-active enzymes that produce or detoxify free radicals and lipid oxidation products. Accordingly, ferroptosis is precisely regulated at multiple levels, including epigenetic, transcriptional, posttranscriptional and posttranslational layers. The transcription factor NFE2L2 plays a central role in upregulating anti-ferroptotic defense, whereas selective autophagy may promote ferroptotic death. Here, we review current knowledge on the integrated molecular machinery of ferroptosis and describe how dysregulated ferroptosis is involved in cancer, neurodegeneration, tissue injury, inflammation, and infection.

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Section: Digestive Systemmentioning

confidence: 99%

Ferroptosis: molecular mechanisms and health implications

et al. 2020

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“…Neutralization of OxPLs was effective to ameliorate NASH by decreasing the expression of a variety of inflammatory chemokines and cytokines such as Ccr2, Ccr5, Ccl6, Cx3cr1, Cxcl14, Il1a, reducing recruitment of monocyte-derived macrophages into the liver and promoting shift of Tim4 − to Tim4 + macrophages that mediated engulfment of apoptotic cells (147). Ferroptosis induced by lipid peroxidation was considered to play a major role in the development of NASH with increased expressions of IL-1β, IL-6, TNF-α, TGF-β, and MCP-1 (148,149).…”

Section: Oxidative Stressmentioning

confidence: 99%

Roles of Hepatic Innate and Innate-Like Lymphocytes in Nonalcoholic Steatohepatitis

Chen

Tian

2020

Front. Immunol.

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Nonalcoholic steatohepatitis (NASH), a progressive form of nonalcoholic fatty liver disease (NAFLD), is accompanied by steatosis, hepatocyte injury and liver inflammation, which has been a health problem in the world as one of the major high risk factors of cirrhosis and hepatocellular carcinoma (HCC). Complex immune responses involving T cells, B cells, Kupffer cells, monocytes, neutrophils, DCs and other innate lymphocytes account for the pathogenesis of NASH; however, the underlying mechanisms have not been clearly elucidated in detail. In the liver, innate and innate-like lymphocytes account for more than two-thirds of total lymphocytes and play an important role in maintaining the immune homeostasis. Therefore, their roles in the progression of NASH deserves investigation. In this review, we summarized murine NASH models for immunological studies, including the diet-induced NASH, chemical-induced NASH and genetic-induced NASH. The role of innate and innate-like lymphocytes including NK cells, ILCs, NKT, γδT and MAIT cells in the progression of NASH were elucidated. Further, the metabolic regulation of the innate immune response was addressed in consideration to explain the molecular mechanisms. Based on the findings of the reviewed studies, strategies of immune intervention are proposed to control the progression of NASH.

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“…In animal models, the severity of NASH was correlated to ferroptosis (death of cells by lipid peroxidation). Elevated arachidonic acid metabolism was reported to promote ferroptosis in methionine-choline deficient diet fed mouse livers, which was further demonstrated by lipid ROS accumulation, morphological change of mitochondria and increased cell death [ 40 ]. Age-related fibrosis in NASH patients was also connected to changes in redox cellular status.…”

Section: Discussionmentioning

confidence: 99%

Serum Malondialdehyde is Associated with Non-Alcoholic Fatty Liver and Related Liver Damage Differentially in Men and Women

et al. 2020

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Background: Non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are associated with increased oxidative stress and lipid peroxidation, but large studies are lacking. The aim was to test the association of malondialdehyde (MDA), as a marker of oxidative damage of lipids, with NAFLD and liver damage markers, and to test the association between dietary vitamins E and C intake and MDA levels. Methods: A cross-sectional study was carried out among subjects who underwent blood tests including FibroMax for non-invasive assessment of NASH and fibrosis. MDA was evaluated by reaction with Thiobarbituric acid and HPLC-fluorescence detection method. NAFLD was diagnosed by abdominal ultrasound. Findings: MDA measurements were available for 394 subjects. In multivariate analysis, the odds for NAFLD were higher with the rise of MDA levels in a dose–response manner, adjusting for age, gender, BMI, and lifestyle factors. Only among men, higher serum MDA was associated of higher odds for NAFLD and NASH and/or fibrosis (OR = 2.59, 95% CI 1.33–5.07, P = 0.005; OR = 2.04, 1.02–4.06, P = 0.043, respectively). Higher vitamin E intake was associated with lower odds of high serum MDA level (OR = 0.28 95% CI 0.13–0.62, P = 0.002). In conclusion, serum MDA is associated with NAFLD and markers of NASH or fibrosis among men. Dietary vitamin E may be protective among women.

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Targeting ferroptosis alleviates methionine‐choline deficient (MCD)‐diet induced NASH by suppressing liver lipotoxicity

Cited by 147 publications

References 54 publications

Ferroptosis: molecular mechanisms and health implications

Ferroptosis: molecular mechanisms and health implications

Roles of Hepatic Innate and Innate-Like Lymphocytes in Nonalcoholic Steatohepatitis

Serum Malondialdehyde is Associated with Non-Alcoholic Fatty Liver and Related Liver Damage Differentially in Men and Women

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