title: Inhibition of Poly(ADP-Ribose) Polymerase-1 Protects Chronic Alcoholic Liver Injury.
abstract: Activation of Kupffer cells (KCs) by gut-derived endotoxin plays a pivotal role in the pathogenesis of alcoholic liver diseases (ALD). Limiting the activation of resident KCs attenuates chronic ethanol-induced liver steatosis and injury. Poly (ADP-ribose) polymerase (PARP)-1 is suggested to play a role in a number of chronic inflammatory diseases. In this study, we found a significant increase of hepatic PARP activity in mice with short-term and long-term ethanol-induced ALD. Male mice on a long-term ethanol diet exhibited severe hepatic steatosis and apoptosis and enhanced KC activation and neutrophil infiltration. However, pharmacologic inhibition of PARP activity or genetic depletion of PARP1 significantly attenuated these detrimental effects in vivo. We found that inhibition of PARP1 effectively reduced hepatic expression of genes involved in lipogenesis and elevated hepatic expression of genes involved in lipolysis. Moreover, limited KC activation and neutrophil infiltration were observed in PARP1 knockout mice or PARP inhibitor-treated mice. Furthermore, in vitro experiments found that LPS-induced macrophage activation was limited by PARP inhibitor, and exposure of ethanol-treated hepatocytes to this conditioned medium further decreased the number of apoptotic and steatotic cells. Taken together, these findings suggest that PARP1 inhibition protects against long-term ethanol-induced liver injury, as indicated by limited hepatocytes steatosis, apoptosis, inflammation levels, and neutrophil infiltration, mainly by limiting KC activation during the initiation of ALD.
authors.affiliation: Clinical Center for Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Clinical Center for Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.affiliation: Clinical Center for Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yunli
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Clinical Center for Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Fengxiao
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Clinical Center for Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Xu
authors.affiliation: Clinical Center for Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Xiangrao
authors.initials: X
authors.lastname: Li
authors.affiliation: Clinical Center for Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Shu
authors.affiliation: Clinical Center for Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Clinical Center for Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Huang
authors.affiliation: Clinical Center for Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: joy_huangdan@163.com.
authors.forename: Dan
authors.initials: D
authors.lastname: Huang
mesh_terms: D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D004731:Endotoxins / Q000378:metabolism; D000431:Ethanol / Q000009:adverse effects; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation; D007728:Kupffer Cells / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000209:etiology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D020011:Protective Agents / Q000494:pharmacology*
chemical_list: D004731:Endotoxins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D020011:Protective Agents; D000431:Ethanol; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1