RRC ID 69477
Author Kim A, Koo JH, Lee JM, Joo MS, Kim TH, Kim H, Jun DW, Kim SG.
Title NRF2-mediated SIRT3 induction protects hepatocytes from ER stress-induced liver injury.
Journal FASEB J
Abstract Chronic endoplasmic reticulum (ER) stress in hepatocytes plays a role in the pathogenesis of nonalcoholic fatty liver disease. Therefore, given the association between oxidative stress, mitochondrial dysfunction, and ER stress, our study investigated the role of NRF2-mediated SIRT3 activation in ER stress. SIRT3, a sirtuin, was predicted as the target of NRF2 based on bioinformatic analyses and animal experiments. Nrf2 abrogation diminished mitochondrial DNA content in hepatocytes with Ppargc1α and Cpt1a inhibition, whereas its overexpression enhanced oxygen consumption. Further, chromatin immunoprecipitation and luciferase reporter assays indicated that NRF2 induced SIRT3 through the antioxidant responsive element (ARE) sites comprising the -641 to -631 bp and -419 to -409 bp regions. In tunicamycin-induced ER stress conditions and liver injury animal models following ER stress, NRF2 levels were highly correlated with SIRT3. Nrf2 deficiency enhanced the tunicamycin-mediated induction of CHOP, which was attenuated by Sirt3 overexpression. Further, Sirt3 delivery to hepatocytes in Nrf2 knockout mice prevented tunicamycin from increasing mortality by decreasing ER stress. SIRT3 was upregulated in livers of patients with nonalcoholic liver diseases, whereas lower SIRT3 expression coincided with more severe disease conditions. Taken together, our findings indicated that NRF2-mediated SIRT3 induction protects hepatocytes from ER stress-induced injury, which may contribute to the inhibition of liver disease progression.
Volume 36(3)
Pages e22170
Published 2022-3-1
DOI 10.1096/fj.202101470R
PMID 35104011
MeSH Animals Antioxidants / metabolism Cell Line DNA, Mitochondrial / metabolism Endoplasmic Reticulum Stress / drug effects Endoplasmic Reticulum Stress / physiology* HEK293 Cells Hepatocytes / drug effects Hepatocytes / metabolism* Humans Liver / drug effects Liver / metabolism Liver Diseases / metabolism* Male Mice Mice, Inbred C57BL Mice, Knockout Mitochondria / drug effects Mitochondria / metabolism NF-E2-Related Factor 2 / metabolism* Oxidative Stress / drug effects Oxidative Stress / physiology Protective Agents / metabolism* Sirtuin 3 / metabolism* Transcription Factor CHOP / metabolism Tunicamycin / pharmacology
IF 4.966
Mice RBRC01390