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ATF4 deficiency protects hepatocytes from oxidative stress via inhibiting CYP2E1 expression.

ABSTRACT: Activating transcription factor (ATF) 4 is involved in the regulation of oxidative stress in fibroblasts and neurons. The role of ATF4 in hepatocytes, however, is unknown. The aim of this study was to investigate the role of ATF4 in hepatocytes in oxidative stress under a high-fat diet (HFD). Here, we showed that palmitate-stimulated reactive oxygen species (ROS) production and triglyceride (TG) accumulation is blocked by ATF4 deficiency in primary hepatocytes. Consistently, HFD-induced oxidative stress, TG accumulation and expression of cytochrome P450, family 2, subfamily, polypeptide 1 (CYP2E1) are also blocked by knocking down ATF4 expression in the mouse liver. This suggests that ATF4 might regulate oxidative stress via CYP2E1 under an HFD. In addition, we observed that expression of CYP2E1 is indirectly regulated by ATF4 in a cAMP-responsive element binding protein (CREB)-dependent manner, which can directly activate the CYP2E1 promoter activity. Notably, ATF4-stimulated ROS production is inhibited in vivo by treatment with diallyl sulphide, a selective CYP2E1 inhibitor. Finally, we showed that ATF4 expression in the liver is responsible for the protective effects against HFD-induced CYP2E1 expression, oxidative stress, and TG accumulation. Taken together, these observations suggest that ATF4 is a novel regulator of oxidative stress as well as accumulation of TG in response to HFD.

SUBMITTER: Wang C

PROVIDER: S-EPMC3916120 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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ATF4 deficiency protects hepatocytes from oxidative stress via inhibiting CYP2E1 expression.

Wang Chunxia C Li Houkai H Meng Qingshu Q Du Ying Y Xiao Fei F Zhang Qian Q Yu Junjie J Li Kai K Chen Shanghai S Huang Zhiying Z Liu Bin B Guo Feifan F

Journal of cellular and molecular medicine 20131106 1

Activating transcription factor (ATF) 4 is involved in the regulation of oxidative stress in fibroblasts and neurons. The role of ATF4 in hepatocytes, however, is unknown. The aim of this study was to investigate the role of ATF4 in hepatocytes in oxidative stress under a high-fat diet (HFD). Here, we showed that palmitate-stimulated reactive oxygen species (ROS) production and triglyceride (TG) accumulation is blocked by ATF4 deficiency in primary hepatocytes. Consistently, HFD-induced oxidativ ...[more]

PMID: 24373582

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Project description:Cellular redox control is maintained by generation of reactive oxygen/nitrogen species balanced by activation of antioxidative pathways. Disruption of redox balance leads to oxidative stress, a central causative event in numerous diseases including heart failure. Redox control in the heart exposed to hemodynamic stress, however, remains to be fully elucidated. Here, we show that production of cardiomyocyte NADPH (nicotinamide adenine dinucleotide phosphate), a key factor in redox regulation, is decreased in pressure overload-induced heart failure. As a consequence, the level of reduced glutathione is downregulated, a change associated with cardiac cell death, fibrosis, and cardiomyopathy. We report that the pentose phosphate pathway (PPP) and mitochondrial serine/glycine/folate metabolic signaling, two major NADPH-generating pathways in the cytosol and mitochondria, respectively, are induced in the heart by pressure overload. We identify ATF4 (activating transcriptional factor 4) as an upstream transcription factor controlling the expression of multiple enzymes in these two pathways. Consistent with this, joint pathway analysis (JPA) of transcriptomic and metabolomic data reveals that ATF4 preferably controls oxidative stress and redox-related pathways. Overexpression of ATF4 in cardiomyocytes in culture leads to a significant increase in NADPH-producing enzymes whereas silencing of ATF4 decreases their expression. Further, stable isotope tracer experiments reveal that ATF4 overexpression in vitro strongly augments metabolic flux within these two pathways. In vivo, cardiomyocyte-specific deletion of ATF4 exacerbates cardiomyopathy in the setting of pressure overload and accelerates the development of heart failure, attributable, at least in part, to an inability to increase the expression of NADPH-generating enzymes. Taken together, our findings reveal that ATF4 plays a critical role in cardiac homeostasis under conditions of hemodynamic stress by governing both cytosolic and mitochondrial production of NADPH.

Project description:The mammalian target of rapamycin (mTOR)/S6K1 signaling pathway controls cell growth and proliferation. To assess the importance of S6K1 in the balance between death and survival in the liver, we have generated immortalized hepatocyte cell lines from wild-type and S6K1-deficient (S6K1(-/-)) mice. In S6K1(-/-) hepatocytes, caspase-8 and the pro-apoptotic protein Bid were constitutively down-regulated as compared with wild-type. Moreover, S6K1(-/-) hepatocytes failed to respond to the apoptotic trigger of death receptor activation. Neither caspase-8 activation nor FLIP(L) degradation in response to tumor necrosis factor alpha (TNF-alpha) or anti-Fas antibody (Jo2) was observed in cells lacking S6K1. Downstream events such as Bid cleavage, cytochrome C release, caspase-3 activation, DNA laddering, as well as the percentage of apoptotic cells were attenuated as compared with wild-type. In addition, the anti-apoptotic protein Bclx(L) was down-regulated in TNF-alpha-treated or Jo2-treated wild-type hepatocytes, but this response was abolished in S6K1(-/-)cells. In vivo, S6K1-deficient mice were protected against concanavalin A-induced apoptosis. The withdrawal of growth factors strongly induced apoptosis in wild-type, but not in S6K1(-/-) hepatocytes. S6K1 deficiency did not decrease Bclx(L)/Bim ratio on serum withdrawal, thereby protecting cells from cytochrome C release and DNA fragmentation. At the molecular level, the lack of S6K1-mediated negative feedback decreased insulin receptor substrate-1 (IRS-1) serine phosphorylation, resulting in activation of survival pathways mediated by phosphatidylinositol 3-kinase/Akt and extracellular signal-regulated kinase (ERK). However, S6K1(-/-) hepatocytes underwent apoptosis on serum withdrawal in combination with phosphatidylinositol 3-kinase (PI3K) or ERK inhibitors.This finding might explain the mechanism of resistance to mTOR inhibitors in cancer treatments and strongly suggests that the inhibition of S6K1 could protect against acute liver failure and, in combination with inhibitors that abrogate the sustained activation of Akt and ERK, could improve the efficacy of hepatocarcinoma (HCC) treatment.

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ATF4 deficiency protects hepatocytes from oxidative stress via inhibiting CYP2E1 expression.

Publications

ATF4 deficiency protects hepatocytes from oxidative stress via inhibiting CYP2E1 expression.

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