title: Proline protects liver from D-galactosamine hepatitis by activating the IL-6/STAT3 survival signaling pathway.
abstract: The oral administration of proline, one of the non-essential amino acids, has been shown to effectively protect the liver from D-galactosamine (GalN)-induced liver injury and to improve the survival rate. The aim of this study was to investigate the mechanism of this protective action of proline. We paid particular attention to the effect of proline on inflammatory activation, regenerative response, and the associated signal transduction in the liver. Male Fischer rats received intraperitoneal injections of GalN (1.4 g/kg) with or without the oral administration of proline (2 g/kg) 1 h before GalN treatment. Liver pathology, plasma indices of inflammation, and the level of proliferative marker in the liver were monitored. The hepatic activation of interleukin-6 (IL-6)/signal transducer and activator of transcription (STAT)-3 pathway, which is downstream of tumor necrosis factor (TNF)-α/nuclear factor-κB, was also studied. GalN induced massive inflammatory expansion in the liver, leading to a high death rate (60 %) more than 72 h after the treatment. Proline administration significantly suppressed inflammatory infiltration in the live after 48 h, which was accompanied by depletion of plasma TNF-α, glutamic oxaloacetic transaminase, and glutamic pyruvic transaminase. The mRNA expression of histone H3, a marker of proliferation, was significantly upregulated in the liver of proline-treated animals. Furthermore, IL-6/STAT-3 pathway, an anti-inflammatory and regenerative signaling pathway, was strongly activated prior to these observations, with the upregulated expression of downstream genes. These results suggest that the tissue-protective mechanism of proline involves the early activation of IL-6/STAT-3 pathway in the liver, with subsequent activation of the regenerative response and suppression of massive inflammatory activation.
authors.affiliation: Research Institute for Health Fundamentals, Ajinomoto Co., Inc, 1-1 Suzuki-cho, Kawasaki-ku, Kawasaki, Kanagawa, 210-8681, Japan. youko_oobayashi@ajinomoto.com
authors.forename: Yoko
authors.initials: Y
authors.lastname: Obayashi
authors.forename: Harumi
authors.initials: H
authors.lastname: Arisaka
authors.forename: Shintaro
authors.initials: S
authors.lastname: Yoshida
authors.forename: Masato
authors.initials: M
authors.lastname: Mori
authors.forename: Michio
authors.initials: M
authors.lastname: Takahashi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D005688:Galactosamine; D006520:Hepatitis, Animal / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D015850:Interleukin-6 / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D011392:Proline / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D015996:Survival Rate
chemical_list: D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D005688:Galactosamine; D011392:Proline