title: Interleukin-18-deficient mice develop dyslipidemia resulting in nonalcoholic fatty liver disease and steatohepatitis.
abstract: We investigated potential pathophysiological relationships between interleukin 18 (IL-18) and dyslipidemia, nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH). Compared with Il18(+/+) mice, IL-18 knockout (Il18(-/-)) mice developed hypercholesterolemia and hyper-high-density-lipoprotein-cholesterolemia as well as hypertriglyceridemia as they aged, and these disorders occurred before the manifestation of obesity and might cause secondary NASH. The analyses of molecular mechanisms involved in the onset of dyslipidemia, NAFLD, and NASH in Il18(-/-) mice identified a number of genes associated with these metabolic diseases. In addition, molecules related to circadian rhythm might affect these extracted genes. The intravenous administration of recombinant IL-18 significantly improved dyslipidemia, inhibited the body weight gain of Il18(+/+) mice, and prevented the onset of NASH. The expression of genes related to these dysfunctions was also affected by recombinant IL-18 administration. In conclusion, this study demonstrated the critical function of IL-18 in lipid metabolism and these findings might contribute to the progress of novel treatments for NAFLD or NASH.
authors.affiliation: Department of Neuropsychiatry, Hyogo College of Medicine, 1-1, Mukogawa, Nishinomiya, Hyogo 663-8501, Japan; Hirakata General Hospital for Developmental Disorders, 2-1-1 Tsudahigashi, Hirakata, Osaka 573-0122, Japan.
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Yamanishi
authors.affiliation: Department of Anatomy and Cell Biology, Hyogo College of Medicine, 1-1, Mukogawa, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Seishi
authors.initials: S
authors.lastname: Maeda
authors.affiliation: Department of Anatomy and Cell Biology, Hyogo College of Medicine, 1-1, Mukogawa, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Sachi
authors.initials: S
authors.lastname: Kuwahara-Otani
authors.affiliation: Hirakata General Hospital for Developmental Disorders, 2-1-1 Tsudahigashi, Hirakata, Osaka 573-0122, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Hirakata General Hospital for Developmental Disorders, 2-1-1 Tsudahigashi, Hirakata, Osaka 573-0122, Japan; Department of Genome Informatics, Osaka University, 3-1, Yamadaoka, Suita 565-0871, Japan.
authors.forename: Momoko
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Department of Neuropsychiatry, Hyogo College of Medicine, 1-1, Mukogawa, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Ikubo
authors.affiliation: DNA-Chip Development Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, 3-1, Yamadaoka, Suita 565-0871, Japan; Department of Molecular Genetics, Research Institute for Microbial Diseases, Osaka University, 3-1, Yamadaoka, Suita 565-0871, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Okuzaki
authors.affiliation: Laboratory of Tumor Immunology and Cell Therapy, Hyogo College of Medicine, 1-1, Mukogawa, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Yosif
authors.initials: Y
authors.lastname: El-Darawish
authors.affiliation: Laboratory of Tumor Immunology and Cell Therapy, Hyogo College of Medicine, 1-1, Mukogawa, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Pathology, Hyogo College of Medicine, 1-1, Mukogawa, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Nakasho
authors.affiliation: DNA-Chip Development Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, 3-1, Yamadaoka, Suita 565-0871, Japan; Department of Molecular Genetics, Research Institute for Microbial Diseases, Osaka University, 3-1, Yamadaoka, Suita 565-0871, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nojima
authors.affiliation: Hirakata General Hospital for Developmental Disorders, 2-1-1 Tsudahigashi, Hirakata, Osaka 573-0122, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Yamanishi
authors.affiliation: Laboratory of Tumor Immunology and Cell Therapy, Hyogo College of Medicine, 1-1, Mukogawa, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Tetsu
authors.initials: T
authors.lastname: Hayakawa
authors.affiliation: Laboratory of Tumor Immunology and Cell Therapy, Hyogo College of Medicine, 1-1, Mukogawa, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Haruki
authors.initials: H
authors.lastname: Okamura
authors.affiliation: Department of Neuropsychiatry, Hyogo College of Medicine, 1-1, Mukogawa, Nishinomiya, Hyogo 663-8501, Japan. Electronic address: hisa1311@hyo-med.ac.jp.
authors.forename: Hisato
authors.initials: H
authors.lastname: Matsunaga
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002940:Circadian Rhythm / Q000187:drug effects; D050171:Dyslipidemias / Q000097:blood / Q000150:complications* / Q000235:genetics / Q000473:pathology; D005234:Fatty Liver / Q000097:blood / Q000150:complications* / Q000235:genetics / Q000473:pathology; D020382:Interleukin-18 / Q000172:deficiency* / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008055:Lipids / Q000096:biosynthesis / Q000097:blood; D008297:Male; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000150:complications* / Q000235:genetics / Q000473:pathology; D009765:Obesity / Q000097:blood / Q000150:complications / Q000235:genetics / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D020382:Interleukin-18; D008055:Lipids; D011994:Recombinant Proteins