期刊
ANTIOXIDANTS & REDOX SIGNALING
卷 27, 期 6, 页码 313-327出版社
MARY ANN LIEBERT, INC
DOI: 10.1089/ars.2016.6716
关键词
glutathione; glutaredoxin; lipids; sirtuin
资金
- NIH [P01 HL068758, R37 HL104017, R01 DK076942, R01 DK103750, R01 HL133013, R01 HL115955]
- NIH CTSI award [1UL1TR 001430]
- NHLBI, National Institutes of Health, Department of Health and Human Services [HHSN 268201000031C, N01-HV-00239]
- American Heart Association [16GRNT27660006]
- European Cooperation in Science and Technology (COST Action) [BM1203/EU-ROS]
- Metabolic Clinical Research Collaborative
- American Heart Association Scientist Postdoctoral Fellowship [15POST21790006]
- NRSA through the Whitaker Cardiovascular Institute postdoctoral training grant [T32 HL70024, 1UL1TR001430]
- American Heart Association Scientist Development Grant [14SDG20140036]
- Strategic Alliance with Institut de Recherche Servier
- Evans Junior Faculty Research Award by the Department of Medicine of Boston University
Aims: Nonalcoholic fatty liver (NAFL) is a common liver disease associated with metabolic syndrome, obesity, and diabetes that is rising in prevalence worldwide. Various molecular perturbations of key regulators and enzymes in hepatic lipid metabolism cause NAFL. However, redox regulation through glutathione (GSH) adducts in NAFL remains largely elusive. Glutaredoxin-1 (Glrx) is a small thioltransferase that removes protein GSH adducts without having direct antioxidant properties. The liver contains abundant Glrx but its metabolic function is unknown. Results: Here we report that normal diet-fed Glrx-deficient mice (Glrx(-/-)) spontaneously develop obesity, hyperlipidemia, and hepatic steatosis by 8 months of age. Adenoviral Glrx repletion in the liver of Glrx(-/-) mice corrected lipid metabolism. Glrx(-/-) mice exhibited decreased sirtuin-1 (SirT1) activity that leads to hyperacetylation and activation of SREBP-1 and upregulation of key hepatic enzymes involved in lipid synthesis. We found that GSH adducts inhibited SirT1 activity in Glrx(-/-) mice. Hepatic expression of nonoxidizable cysteine mutant SirT1 corrected hepatic lipids in Glrx(-/-) mice. Wild-type mice fed high-fat diet develop metabolic syndrome, diabetes, and NAFL within several months. Glrx deficiency accelerated high-fat-induced NAFL and progression to steatohepatitis, manifested by hepatic damage and inflammation. Innovation: These data suggest an essential role of hepatic Glrx in regulating SirT1, which controls protein glutathione adducts in the pathogenesis of hepatic steatosis. Conclusion: We provide a novel redox-dependent mechanism for regulation of hepatic lipid metabolism, and propose that upregulation of hepatic Glrx may be a beneficial strategy for NAFL.
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