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It has emerged that hepatocyte necroptosis plays a critical role in chronic alcoholic liver disease (ALD). Our previous study has identified that the beneficial therapeutic effect of curcumin on alcohol-caused liver injury might be attributed to activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), whereas the role of curcumin in regulating necroptosis and the underlying mechanism remain to be determined. We first found that chronic alcohol consumption triggered obvious hepatocyte necroptosis, leading to increased expression of receptor-interacting protein 1, receptor-interacting protein 3, high-mobility group box 1, and phosphorylated mixed lineage kinase domain-like in murine livers. Curcumin dose-dependently ameliorated hepatocyte necroptosis and alleviated alcohol-caused decrease in hepatic Nrf2 expression in alcoholic mice. Then Nrf2 shRNA lentivirus was introduced to generate Nrf2-knockdown mice. Our results indicated that Nrf2 knockdown aggravated the effects of alcohol on liver injury and necroptosis and even abrogated the inhibitory effect of curcumin on necroptosis. Further, activated Nrf2 by curcumin inhibited p53 expression in both livers and cultured hepatocytes under alcohol stimulation. The next in vitro experiments, similar to in vivo ones, revealed that although Nrf2 knockdown abolished the suppression of curcumin on necroptosis of hepatocytes exposed to ethanol, p53 siRNA could clearly rescued the relative effect of curcumin. In summary, for the first time, we concluded that curcumin attenuated alcohol-induced hepatocyte necroptosis in a Nrf2/p53-dependent mechanism. These findings make curcumin an excellent candidate for ALD treatment and advance the understanding of ALD mechanisms associated with hepatocyte necroptosis.

Alcoholic liver disease (ALD) is a common health problem worldwide, characterized by aberrant accumulation of lipid in hepatocytes. Inhibition of lipid accumulation has been well recognized as a promising strategy for ALD. Previous studies showed that curcumin has potential effect on ALD by regulating oxidative stress and ethanol metabolism. However, the effects of curcumin on lipid accumulation and its mechanism remain unclear. Recent researches have indicated that farnesoid X receptor (FXR) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) have excellent effects on reducing lipid deposition. This study demonstrated that curcumin alleviated ethanol-induced liver injury by ameliorating activities of serum marker enzymes and inflammation. Moreover, curcumin alleviated the symptom of hyperlipidemia and hepatic steatosis via modulating the expression of sterol regulatory elementbinding protein-1c, fatty acid synthase, and peroxisome proliferator-activated receptor-alpha as well as the activity of carnitine palmitoyltransferase 1. Additionally, curcumin induced the expression of Nrf2 and FXR in liver, strongly implying close relationship between inhibitory effect of curcumin on hepatic steatosis and the above two genes. The following in vitro experiments further verified the protective effects of curcumin against hepatotoxicity and lipid accumulation in hepatocytes induced by ethanol. Gain-or loss-of-function analyses revealed Nrf2 and FXR mediated the effect of curcumin on lipid deposition in hepatocytes, and curcumin modulated Additional Supporting Information may be found in the online version of this article.Abbreviations: ALD, alcoholic liver disease; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPT1, carnitine palmitoyltransferase 1; DMEM, Dulbecco's modified eagle medium; DMSO, dimethylsulfoxide; FAS, fatty acid synthase; FBS, fetal bovine serum; FXR, farnesoid X receptor; GAPDH, glyceraldehyde phosphate dehydrogenase; H&E, haematoxylin-eosin; HDL-C, high-density lipoprotein-cholesterol; LDH, lactate dehydrogenase; LDL-C, low-density lipoprotein-cholesterol; MTT, 3-(4,5-dimethylthiazol-2-yl)22,5-diphenyltetrazolium bromide; NF-jB, nuclear factor-kappa B; Nrf2, nuclear factor (erythroid-derived 2)-like 2; PPAR-a, peroxisome proliferator-activated receptor-alpha; SREBP-1c, sterol regulatory element-binding protein-1c; TC, total cholesterol; TG, triglyceride; TNF-a, tumor necrosis factor-alpha. 645the expression of FXR mediated by Nrf2. Collectively, we drew a conclusion that curcumin attenuated ALD by modulating lipid deposition in hepatocytes via a Nrf2/FXR activationdependent mechanism. The findings make curcumin a potential agent for ALD and broaden the horizon of the molecular mechanism involved. V C 2015 IUBMB Life, 67(8):645-658, 2015