title: Glycine prevents metabolic steatohepatitis in diabetic KK-Ay mice through modulation of hepatic innate immunity.
abstract: Strategies for prevention and treatment of nonalcoholic steatohepatitis remain to be established. We evaluated the effect of glycine on metabolic steatohepatitis in genetically obese, diabetic KK-Aymice. Male KK-Aymice were fed a diet containing 5% glycine for 4 wk, and liver pathology was evaluated. Hepatic mRNA levels for lipid-regulating molecules, cytokines/chemokines, and macrophage M1/M2 markers were determined by real-time RT-PCR. Hepatic expression of natural killer (NK) T cells was analyzed by flow cytometry. Body weight gain was significantly blunted and development of hepatic steatosis and inflammatory infiltration were remarkably prevented in mice fed the glycine-containing diet compared with controls. Indeed, hepatic induction levels of molecules related to lipogenesis were largely blunted in the glycine diet-fed mice. Elevations of hepatic mRNA levels for TNFα and chemokine (C-C motif) ligand 2 were also remarkably blunted in the glycine diet-fed mice. Furthermore, suppression of hepatic NK T cells was reversed in glycine diet-fed KK-Aymice, and basal hepatic expression levels of NK T cell-derived cytokines, such as IL-4 and IL-13, were increased. Moreover, hepatic mRNA levels of arginase-1, a marker of macrophage M2 transformation, were significantly increased in glycine diet-fed mice. In addition, dietary glycine improved glucose tolerance and hyperinsulinemia in KK-Aymice. These observations clearly indicate that glycine prevents maturity-onset obesity and metabolic steatohepatitis in genetically diabetic KK-Aymice. The underlying mechanisms most likely include normalization of hepatic innate immune responses involving NK T cells and M2 transformation of Kupffer cells. It is proposed that glycine is a promising immunonutrient for prevention and treatment of metabolic syndrome-related nonalcoholic steatohepatitis.
authors.affiliation: Department of Gastroenterology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Shiori
authors.initials: S
authors.lastname: Takashima
authors.affiliation: Department of Gastroenterology, Juntendo University Graduate School of Medicine, Tokyo, Japan ikejima@juntendo.ac.jp.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Ikejima
authors.affiliation: Department of Gastroenterology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Arai
authors.affiliation: Department of Gastroenterology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Yokokawa
authors.affiliation: Department of Gastroenterology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kon
authors.affiliation: Department of Gastroenterology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Shunhei
authors.initials: S
authors.lastname: Yamashina
authors.affiliation: Department of Gastroenterology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Sumio
authors.initials: S
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D048909:Diabetes Complications / Q000188:drug therapy* / Q000276:immunology / Q000517:prevention & control; D019587:Dietary Supplements; D005234:Fatty Liver / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology / Q000517:prevention & control; D005998:Glycine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007113:Immunity, Innate; D007155:Immunologic Factors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology; D008099:Liver / Q000187:drug effects* / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008297:Male; D008810:Mice, Inbred C57BL; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D007155:Immunologic Factors; D018793:Interleukin-13; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D005998:Glycine
keywords: Kupffer cells; adipokine; metabolic syndrome; natural killer T cells; nonalcoholic steatohepatitis