Abstract

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 liver-specific 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.

Highlights

  • 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]

  • ATF4 liver-specific knock-out (ALKO) Mice Are Resistant to Ethanol-induced Liver Steatosis—The elevated expression of Activating transcription factor 4 (ATF4) in response to ethanol exposure indicates a possible involvement of ATF4 in ethanol-induced liver steatosis

  • 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]

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Summary

Introduction

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]. 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). 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]. A role of ATF4 in ethanol-induced liver steatosis, has not previously been studied. AMPK [20], a kinase that plays a central role in ethanol-induced liver steatosis (6 – 8). We hypothesized that ATF4 may play a role in ethanol-induced liver steatosis. The aim of our current study is to investigate this possibility and elucidate the underlying mechanisms

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