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J Pharmacol Exp Ther. 2018 Mar;364(3):452-461. doi: 10.1124/jpet.117.243105. Epub 2018 Jan 9.

Poly(ADP-Ribose) Polymerase Inhibitor PJ34 Attenuated Hepatic Triglyceride Accumulation in Alcoholic Fatty Liver Disease in Mice.

Author information

1
College of Medical Laboratory Science and Technology, Harbin Medical University, Daqing, Heilongjiang, China (S.H., B.Z., Y.C., Y.L., X.L., Z.B., Z.W.); Fuxin Center Hospital, Fuxin, Jilin, China (H.L.); and Department of Kinesiology and Nutrition, University of Illinois, Chicago, Illinois (Z.S.).
2
College of Medical Laboratory Science and Technology, Harbin Medical University, Daqing, Heilongjiang, China (S.H., B.Z., Y.C., Y.L., X.L., Z.B., Z.W.); Fuxin Center Hospital, Fuxin, Jilin, China (H.L.); and Department of Kinesiology and Nutrition, University of Illinois, Chicago, Illinois (Z.S.) wangzhigang@hmudq.edu.cn.

Abstract

Poly(ADP-ribose) polymerase (PARP) is an NAD-consuming enzyme and its specific role in the pathogenesis of alcoholic fatty liver disease (AFLD) remains elusive. In this study, we applied PJ34 [N-(5,6-dihydro-6-oxo-2-phenanthridinyl)-2-acetamide hydrochloride] to inhibit hepatic PARP activity to examine the corresponding pathologic alteration in AFLD in mice and the underlying molecular mechanism. We found that PJ34 decreased the intracellular triglyceride (TG) content in hepatocytes. Moreover, PJ34 suppressed the gene expression of diglyceride acyltransferases DGAT1 and DGAT2 and elevated intracellular NAD+ levels in hepatocytes. These mechanistic observations were validated in alcohol-fed mice injected with PJ34 intraperitoneally. Our results indicate that the PJ34 injection attenuated hepatic TG accumulation in alcohol-fed mice. Furthermore, PJ34 injection lowered the gene expression of hepatic sterol regulatory element binding protein 1c, DGAT1, and DGAT2, whereas PJ34 injection augmented hepatic NAD+ levels in alcohol-fed mice. Finally, nicotinamide riboside supplementation alleviated hepatic TG accumulation in alcohol-fed mice. These data indicate that applying PARP-specific inhibitor PJ34 by intraperitoneal injection attenuated hepatic NAD+ depletion and TG accumulation in alcohol-fed mice and may be a potential candidate for use in AFLD therapy.

PMID:
29317476
DOI:
10.1124/jpet.117.243105

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