title: The Detrimental Role Played by Lipocalin-2 in Alcoholic Fatty Liver in Mice.
abstract: We have previously shown that the ethanol-mediated elevation of lipocaline-2 (LCN2) is closely associated with the development of alcoholic fatty liver disease (AFLD) in mice. Herein, we aimed to understand the functional significance of LCN2 induction by ethanol and to explore its underlying mechanisms. We evaluated the effects of LCN2 in an in vitro cellular alcoholic steatosis model and in an animal study using wild-type and LCN2 knockout mice fed for 4 weeks with an ethanol-supplemented Lieber-DeCarli diet. In the cellular model of alcoholic steatosis, recombinant LCN2 or overexpression of LCN2 exacerbated ethanol-induced fat accumulation, whereas knocking down LCN2 prevented steatosis in hepatocytes exposed to ethanol. Consistently, removal of LCN2 partially but significantly alleviated alcoholic fatty liver injury in mice. Mechanistically, LCN2 mediates detrimental effects of ethanol in the liver via disrupted multiple signaling pathways, including aberrant nicotinamide phosphoribosyltransferase-sirtuin 1 axis, perturbed endocrine metabolic regulatory fibroblast growth factor 15/19 signaling, and impaired chaperone-mediated autophagy. Finally, compared with healthy human livers, liver samples from patients with AFLD had lower gene expression of several LCN2-regualted molecules. Our study demonstrated a pivotal and causal role of LCN2 in the development of AFLD and suggested that targeting the LCN2 could be of great value for the treatment of human AFLD.
authors.affiliation: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio.
authors.forename: Alvin
authors.initials: A
authors.lastname: Jogasuria
authors.affiliation: Department of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, Tampa, Florida.
authors.forename: Huquan
authors.initials: H
authors.lastname: Yin
authors.affiliation: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland.
authors.forename: Ming-Jiang
authors.initials: MJ
authors.lastname: Xu
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio; Department of Biology, School of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Xudong
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio; Department of Anatomy, School of Fundamental Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
authors.forename: Jiayou
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio.
authors.forename: Chunki
authors.initials: C
authors.lastname: Kim
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio.
authors.forename: Jiashin
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio.
authors.forename: Kwangwon
authors.initials: K
authors.lastname: Lee
authors.affiliation: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland.
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio. Electronic address: myou@neomed.edu.
authors.forename: Min
authors.initials: M
authors.lastname: You
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D005235:Fatty Liver, Alcoholic / Q000378:metabolism*; D006801:Humans; D000071068:Lipocalin-2 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction
chemical_list: D000071068:Lipocalin-2