title: Pigment Epithelium-Derived Factor (PEDF) Prevents Hepatic Fat Storage, Inflammation, and Fibrosis in Dietary Steatohepatitis of Mice.
abstract: Pigment epithelium-derived factor (PEDF) has been shown to be a potent inhibitor of inflammation through its anti-oxidative property. Since oxidative response is considered to play the pivotal role of the development and progression of nonalcoholic steatohepatitis (NASH), it is conceivable that PEDF may play a protective role against NASH. In this study, we examined whether administration of PEDF slowed the progression of NASH in mice models.
  
  
  
  Mice were fed methionine- and choline-deficient (MCD) diet with or without intramuscular administration of adenovirus-expressing PEDF (Ad-PEDF). Effects of PEDF administration on NASH were histologically and biochemically evaluated.
  
  
  
  Administration of Ad-PEDF significantly decreased hepatic fat storage as well as serum levels of ALT in MCD diet-fed mice. Dihydroethidium staining showed that MCD diet-triggered oxidative stress was reduced in the liver of Ad-PEDF-administered mice compared to that of PBS- or Ad-LacZ-administered mice. Activation of Kupffer cells and hepatic fibrosis was also inhibited by Ad-PEDF administration. Quantitative real-time RT-PCR revealed that MCD diet up-regulated expressions of TNF-α, IL-1β, IL-6, TGF-β, collagen-1, and collagen-3 mRNA, which were also attenuated with Ad-PEDF administration, whereas MCD diet-induced down-regulation of expressions of PPAR-γ mRNA was restored with Ad-PEDF administration. Furthermore, immunoblotting analysis showed that MCD diet-induced up-regulation of NADPH oxidase components was significantly decreased in Ad-PEDF-administered mice.
  
  
  
  The present results demonstrated for the first time that PEDF could slow the development and progression of steatohepatitis through the suppression of steatosis and inflammatory response in MCD diet-fed mice. Our study suggests that PEDF supplementation may be a novel therapeutic strategy for the treatment of NASH.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan. tayoshi@med.kurume-u.ac.jp.|Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, Kurume Clinical Pharmacology Clinic, 67 Asahi-Machi, Kurume, 830-0011, Japan. tayoshi@med.kurume-u.ac.jp.
authors.forename: Takafumi
authors.identifier: 0000-0001-6806-6215
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Department of Diagnostic Pathology, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Akiba
authors.affiliation: Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Matsui
authors.affiliation: Nakamura Clinic, Wakamatsu-ku, Kitakyushu, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.|Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, Kurume Clinical Pharmacology Clinic, 67 Asahi-Machi, Kurume, 830-0011, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Hisamoto
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.|Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, Kurume Clinical Pharmacology Clinic, 67 Asahi-Machi, Kurume, 830-0011, Japan.
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Abe
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.|Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, Kurume Clinical Pharmacology Clinic, 67 Asahi-Machi, Kurume, 830-0011, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ikezono
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.|Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, Kurume Clinical Pharmacology Clinic, 67 Asahi-Machi, Kurume, 830-0011, Japan.
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Wada
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.|Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, Kurume Clinical Pharmacology Clinic, 67 Asahi-Machi, Kurume, 830-0011, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Iwamoto
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.|Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, Kurume Clinical Pharmacology Clinic, 67 Asahi-Machi, Kurume, 830-0011, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.|Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, Kurume Clinical Pharmacology Clinic, 67 Asahi-Machi, Kurume, 830-0011, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Koga
authors.affiliation: Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Sho-Ichi
authors.initials: SI
authors.lastname: Yamagishi
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.|Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, Kurume Clinical Pharmacology Clinic, 67 Asahi-Machi, Kurume, 830-0011, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Torimura
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000273:Adipose Tissue / Q000473:pathology*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D002796:Choline Deficiency / Q000150:complications; D024042:Collagen Type I / Q000235:genetics; D024061:Collagen Type III / Q000235:genetics; D004032:Diet; D004195:Disease Models, Animal; D015536:Down-Regulation; D005136:Eye Proteins / Q000235:genetics / Q000494:pharmacology*; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D007273:Injections, Intramuscular; D053583:Interleukin-1beta / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D007728:Kupffer Cells; D008103:Liver Cirrhosis / Q000517:prevention & control; D008297:Male; D008715:Methionine / Q000008:administration & dosage / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics / Q000494:pharmacology*; D018384:Oxidative Stress; D047495:PPAR gamma / Q000235:genetics; D011480:Protease Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism*; D015843:Serpins / Q000235:genetics / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D015854:Up-Regulation; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D000410:Alanine Transaminase; D024042:Collagen Type I; D024061:Collagen Type III; D005136:Eye Proteins; D053583:Interleukin-1beta; D015850:Interleukin-6; D008715:Methionine; D019255:NADPH Oxidases; D009414:Nerve Growth Factors; D047495:PPAR gamma; D011480:Protease Inhibitors; D012333:RNA, Messenger; D015843:Serpins; D014409:Tumor Necrosis Factor-alpha; D000099174:Pigment Epithelium-Derived Factor
keywords: Oxidative stress; Pigment epithelium-derived factor; Steatohepatitis