ATF4 and the integrated stress response are induced by ethanol and cytochrome P450 2E1 in human hepatocytes

Magne, Laurent; Blanc, Étienne; Legrand, Béatrice; Lucas, Danièle; Barouki, Robert; Rouach, Hélène; Garlatti, Michèle

doi:10.1016/j.jhep.2010.07.023

Cited by 58 publications

(47 citation statements)

References 45 publications

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“…In this study, we showed that knock-out of ATF4 in the liver has no effect on hepatic TG accumulation under a pair-fed control diet, but it significantly prevented ethanol-induced liver steato- sis. Consistent with our work, other studies showed that CYP2E1 (cytochrome P450 2e1) regulates ethanol-induced liver steatosis, associated with corresponding changes in ATF4 expression (22). In addition, we believe that the effect of ATF4 is a hepatocyte cell-autonomous response because similar results were obtained in our in vitro study using AML-12 cells.…”

Section: Discussionsupporting

confidence: 93%

“…Although it has been shown that ATF4 expression is induced by ethanol (22,23,24,34), a direct effect of ATF4 on alcoholic liver steatosis has not been described previously. Furthermore, the knowledge about tissue-specific function of ATF4 is very limited, except for a study showing that ATF4 expressed in the osteoblast or liver is important for blood glucose control (36).…”

Section: Discussionmentioning

confidence: 87%

“…A role of ATF4 in ethanol-induced liver steatosis, however, has not previously been studied. Interestingly, ATF4 expression is induced by ethanol exposure in human hepatocytes (22), bone marrow stromal cells (23), and rat livers (24). Furthermore, ATF4 inhibits the activity of hypothalamic AMPK (20), a kinase that plays a central role in ethanol-induced liver steatosis (6 -8).…”

mentioning

confidence: 99%

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Liver-specific Gene Inactivation of the Transcription Factor ATF4 Alleviates Alcoholic Liver Steatosis in Mice

Li¹,

Xiao²,

et al. 2016

Journal of Biological Chemistry

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Although numerous biological functions of the activating transcription factor 4 (ATF4) have been identified, a direct effect of ATF4 on alcoholic liver steatosis has not been described previously. The aim of our current study is to investigate the role of ATF4 in alcoholic liver steatosis and elucidate the underlying mechanisms. Here, we showed that the expression of ATF4 is induced by ethanol in hepatocytes in vitro and in vivo, and liverspecific ATF4 knock-out mice are resistant to ethanol-induced liver steatosis, associated with stimulated hepatic AMP-activated protein kinase (AMPK) activity. Furthermore, adenovirus-mediated AMPK knockdown significantly reversed the suppressive effects of ATF4 deficiency on ethanol-induced liver steatosis in mice. In addition, ethanol-fed ATF4 knock-out mice exhibit AMPK-dependent inhibition of fatty acid synthase and stimulation of carnitine palmitoyltransferase 1 (CPT1) in the liver. Moreover, hepatic Tribbles homolog 3 (TRB3) expression was stimulated by ethanol in an ATF4-dependent manner, and adenovirus-mediated TRB3 knockdown blocked ATF4-dependent ethanol-induced AMPK inhibition and triglyceride accumulation in AML-12 cells. Finally, TRB3 directly interacted with AMPK to suppress its phosphorylation. Taken together, these results identify the ATF4-TRB3-AMPK axis as a novel pathway responsible for ethanol-induced liver steatosis.People consuming excessive amounts of alcohol for prolonged periods suffer from alcoholic liver disease, which encompasses fatty liver, hepatic inflammation and necrosis, progressive fibrosis, and hepatocellular carcinoma (1). Alcoholic fatty liver is the early stage of alcoholic liver disease, characterized by increased accumulation of fat in the liver, which is usually caused by increased free fatty acid (FFA) 4 uptake, augmented de novo lipogenesis, decreased ␤-oxidation, and/or impaired triglyceride (TG) export (2). Studies have identified some important regulators for ethanol-induced liver steatosis, including sirtuin 1 (SIRT1) (3), sterol regulatory element-binding protein 1 (SREBP-1) (4), peroxisome proliferator-activated receptor ␥ coactivator 1-␣ (PGC-1␣) (5), and 5Ј-adenosine monophosphate-activated protein kinase (AMPK) (6 -8).Among them, AMPK is one of the most important regulators (6 -8). AMPK is a heterotrimeric complex consisting of a catalytic ␣ subunit and two regulatory ␤/␥ subunits. It acts as a key metabolic "switch" by phosphorylating target enzymes involved in lipid metabolism, such as acetyl-CoA carboxylase (ACC) (9). Malonyl-CoA, the product of ACC, is both a precursor for fatty acid biosynthesis and a potent inhibitor of ␤-oxidation at the step regulated by carnitine palmitoyltransferase I (10). AMPK activity is suppressed under ethanol exposure (6) and activation of AMPK by its activator (5-aminoimidazole-4-carboxamide 1-␤-D-ribofuranoside) or metformin prevents ethanol-induced liver steatosis (11, 12). However, the molecular mechanisms underlying ethanol suppression of AMPK activity remain largely unknown. Activating...

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 87%

mentioning

confidence: 99%

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Liver-specific Gene Inactivation of the Transcription Factor ATF4 Alleviates Alcoholic Liver Steatosis in Mice

Li¹,

Xiao²,

et al. 2016

Journal of Biological Chemistry

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“…ER stress has been reported to contribute to alcohol-induced liver injury and the progression of alcoholic liver disease in both animal and cell models [35][36][37][38].…”

Section: Er Stress Induces Apoptosismentioning

confidence: 99%

Acrolein is a critical mediator of alcohol-induced liver and intestinal injury in alcoholic liver disease.

Chen¹,

Weiyang²

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“…ER stress has been reported to contribute to alcohol-induced liver injury and the progression of alcohol live disease in both animal and cell models [30][31][32][33].…”

Section: Er Stress Induces Apoptosismentioning

confidence: 99%

Pathogenic role of acrolein in alcoholic liver disease.

Chen¹

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ATF4 and the integrated stress response are induced by ethanol and cytochrome P450 2E1 in human hepatocytes

Cited by 58 publications

References 45 publications

Liver-specific Gene Inactivation of the Transcription Factor ATF4 Alleviates Alcoholic Liver Steatosis in Mice

Liver-specific Gene Inactivation of the Transcription Factor ATF4 Alleviates Alcoholic Liver Steatosis in Mice

Acrolein is a critical mediator of alcohol-induced liver and intestinal injury in alcoholic liver disease.

Pathogenic role of acrolein in alcoholic liver disease.

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