1. Sestrin Proteins Protect Against Lipotoxicity-Induced Oxidative Stress in the Liver via Suppression of C-Jun N-Terminal KinasesSummary
- Author
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Menghao Huang, Kushan Chowdhury, Zhigang Fang, X. Charlie Dong, Ming O. Li, Suthat Liangpunsakul, and Hyeong-Geug Kim
- Subjects
0301 basic medicine ,Sestrins ,MPO, myeloperoxidase ,Mitogen-Activated Protein Kinase Kinase 7 ,RC799-869 ,DMSO, dimethyl sulfoxide ,FoxO, forkhead box O ,Sesn1/2/3, sestrin1/2/3 ,medicine.disease_cause ,TKO, triple knockout ,Mice ,PCR, polymerase chain reaction ,0302 clinical medicine ,GSH, glutathione ,Phosphorylation ,NF-κB, nuclear factor kappa B ,Original Research ,Cat, catalase ,Mice, Knockout ,Sestrin ,Gpx3, glutathione peroxidase 3 ,Il6, interleukin 6 ,WD, Western diet ,biology ,Chemistry ,Kinase ,Fatty liver ,Tgfbr1, transforming growth factor beta receptor 1 ,Gastroenterology ,Col1a1, collagen type 1 alpha 1 ,Nox1, NADPH oxidase 1 ,Diseases of the digestive system. Gastroenterology ,Dgat2, diacylglycerol O-acyltransferase 2 ,Cell biology ,Keap1, Kelch-like ECH-associated protein 1 ,C-Jun N-Terminal Kinase ,Liver ,Lipotoxicity ,c-Jun N-terminal kinases ,JNK, c-Jun N-terminal kinase ,030211 gastroenterology & hepatology ,Disease Susceptibility ,Signal transduction ,NASH, nonalcoholic steatohepatitis ,Gss, glutathione synthetase ,Pdgfrb, platelet-derived growth factor receptor beta ,Timp1, tissue inhibitor of metalloproteinase 1 ,Fasn, fatty acid synthase ,Fatty Liver Disease ,Sod, superoxide dismutase ,Acta2, smooth muscle actin alpha 2 ,ER, endoplasmic reticulum ,PA, palmitic acid ,03 medical and health sciences ,4-HNE, 4-hydroxynonenal ,MKK, mitogen-activated protein kinase kinase ,medicine ,Animals ,Humans ,Srebp, sterol regulatory element-binding protein ,Protein kinase A ,KD, knockdown ,MDA, malondialdehyde ,Inflammation ,KO, knockout ,Hepatology ,NRF2, nuclear factor erythroid 2-related like 2 ,JNK Mitogen-Activated Protein Kinases ,Lipid Metabolism ,medicine.disease ,Tgfb1, transforming growth factor beta 1 ,WT, wild-type ,mTORC, mechanistic target of rapamycin complex ,Fatty Liver ,AMPK, AMP-activated protein kinase ,Disease Models, Animal ,Oxidative Stress ,Scd1, stearoyl-CoA desaturase 1 ,030104 developmental biology ,Gene Expression Regulation ,Cytoprotection ,Hepatocytes ,biology.protein ,BSA, bovine serum albumin ,SD, standard deviation ,DHE, dihydroethidium ,PERK, protein kinase R-like endoplasmic reticulum kinase ,Tnf, tumor necrosis factor ,Biomarkers ,Oxidative stress - Abstract
Background & Aims Sestrin 1/2/3 (Sesn1/2/3) belong to a small family of proteins that have been implicated in the regulation of metabolic homeostasis and oxidative stress. However, the underlying mechanisms remain incompletely understood. The aim of this work was to illustrate the collective function of Sesn1/2/3 in the protection against hepatic lipotoxicity. Methods We used Sesn1/2/3 triple knockout (TKO) mouse and cell models to characterize oxidative stress and signal transduction under lipotoxic conditions. Biochemical, histologic, and physiological approaches were applied to illustrate the related processes. Results After feeding with a Western diet for 8 weeks, TKO mice developed remarkable metabolic associated fatty liver disease that was manifested by exacerbated hepatic steatosis, inflammation, and fibrosis compared with wild-type counterparts. Moreover, TKO mice exhibited higher levels of hepatic lipotoxicity and oxidative stress. Our biochemical data revealed a critical signaling node from sestrins to c-Jun N-terminal kinases (JNKs) in that sestrins interact with JNKs and mitogen-activated protein kinase kinase 7 and suppress the JNK phosphorylation and activity. In doing so, sestrins markedly reduced palmitate-induced lipotoxicity and oxidative stress in both mouse and human hepatocytes. Conclusions The data from this study suggest that Sesn1/2/3 play an important role in the protection against lipotoxicity-associated oxidative stress and related pathology in the liver., Graphical abstract
- Published
- 2021