title: β-Lapachone alleviates alcoholic fatty liver disease in rats.
abstract: Alcohol-induced liver injury is the most common liver disease in which fatty acid metabolism is altered. It is thought that altered NAD(+)/NADH redox potential by alcohol in the liver causes fatty liver by inhibiting fatty acid oxidation and the activity of tricarboxylic acid cycle reactions. β-Lapachone (βL), a naturally occurring quinone, has been shown to stimulate fatty acid oxidation in an obese mouse model by activating adenosine monophosphate-activated protein kinase (AMPK). In this report, we clearly show that βL reduced alcohol-induced hepatic steatosis and induced fatty acid oxidizing capacity in ethanol-fed rats. βL treatment markedly decreased hepatic lipids while serum levels of lipids and lipoproteins were increased in rats fed ethanol-containing liquid diets with βL administration. Furthermore, inhibition of lipolysis, enhancement of lipid mobilization to mitochondria and upregulation of mitochondrial β-oxidation activity in the soleus muscle were observed in ethanol/βL-treated animals compared to the ethanol-fed rats. In addition, the activity of alcohol dehydrogenase, but not aldehyde dehydrogenase, was significantly increased in rats fed βL diets. βL-mediated modulation of NAD(+)/NADH ratio led to the activation of AMPK signaling in these animals.
  
  
  CONCLUSIONS
  Our results suggest that improvement of fatty liver by βL administration is mediated by the upregulation of apoB100 synthesis and lipid mobilization from the liver as well as the direct involvement of βL on NAD(+)/NADH ratio changes, resulting in the activation of AMPK signaling and PPARα-mediated β-oxidation. Therefore, βL-mediated alteration of NAD(+)/NADH redox potential may be of potential therapeutic benefit in the clinical setting.
authors.affiliation: Department of Pharmacology, Metabolic Diseases and Cell Signaling Laboratory, Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon 301-474, South Korea.
authors.forename: Sanghee
authors.initials: S
authors.lastname: Shin
authors.affiliation: Department of Pharmacology, Metabolic Diseases and Cell Signaling Laboratory, Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon 301-474, South Korea.
authors.forename: Jisoo
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Pharmacology, Metabolic Diseases and Cell Signaling Laboratory, Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon 301-474, South Korea; Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Shaanxi, China.
authors.forename: Yuwen
authors.initials: Y
authors.lastname: Li
authors.affiliation: Mazence Inc. R&D Center, Suwon 443-813, South Korea.
authors.forename: Ki Nam
authors.initials: KN
authors.lastname: Min
authors.affiliation: Department of Pharmacology, Metabolic Diseases and Cell Signaling Laboratory, Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon 301-474, South Korea.
authors.forename: Gyeyeong
authors.initials: G
authors.lastname: Kong
authors.affiliation: Department of Pharmacology, Metabolic Diseases and Cell Signaling Laboratory, Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon 301-474, South Korea.
authors.forename: Gang Min
authors.initials: GM
authors.lastname: Hur
authors.affiliation: Department of Pathology, College of Medicine, Chungnam National University, Daejeon 301-131, South Korea.
authors.forename: Jin Man
authors.initials: JM
authors.lastname: Kim
authors.affiliation: Internal Medicine, College of Medicine, Chungnam National University, Daejeon 301-131, South Korea.
authors.forename: Minho
authors.initials: M
authors.lastname: Shong
authors.affiliation: Mazence Inc. R&D Center, Suwon 443-813, South Korea.
authors.forename: Min-Suk
authors.initials: MS
authors.lastname: Jung
authors.affiliation: Mazence Inc. R&D Center, Suwon 443-813, South Korea.
authors.forename: Jong Kook
authors.initials: JK
authors.lastname: Park
authors.affiliation: Mazence Inc. R&D Center, Suwon 443-813, South Korea.
authors.forename: Kyeong-Hoon
authors.initials: KH
authors.lastname: Jeong
authors.affiliation: Mazence Inc. R&D Center, Suwon 443-813, South Korea.
authors.forename: Myoung Gyu
authors.initials: MG
authors.lastname: Park
authors.affiliation: Mazence Inc. R&D Center, Suwon 443-813, South Korea.
authors.forename: Tae Hwan
authors.initials: TH
authors.lastname: Kwak
authors.affiliation: Centre for Experimental Medicine School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, BT12 6BA Northern Ireland, UK.
authors.forename: Derek P
authors.initials: DP
authors.lastname: Brazil
authors.affiliation: Department of Pharmacology, Metabolic Diseases and Cell Signaling Laboratory, Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon 301-474, South Korea. Electronic address: insulin@cnu.ac.kr.
authors.forename: Jongsun
authors.initials: J
authors.lastname: Park
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000426:Alcohol Dehydrogenase / Q000378:metabolism; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D000431:Ethanol / Q000633:toxicity*; D005227:Fatty Acids / Q000378:metabolism; D005235:Fatty Liver, Alcoholic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology; D015227:Lipid Peroxidation; D008297:Male; D009285:Naphthoquinones / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D018894:Reverse Transcriptase Inhibitors; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D005227:Fatty Acids; D009285:Naphthoquinones; D018894:Reverse Transcriptase Inhibitors; D000431:Ethanol; C014638:beta-lapachone; D000426:Alcohol Dehydrogenase; D000444:Aldehyde Dehydrogenase; D055372:AMP-Activated Protein Kinases
keywords: AMPK; Fatty liver diseases; Metabolic syndrome; PPARα; β-Lapachone