title: Wheat-bran autolytic peptides containing a branched-chain amino acid attenuate non-alcoholic steatohepatitis via the suppression of oxidative stress and the upregulation of AMPK/ACC in high-fat diet-fed mice.
abstract: Whole-wheat intake is known to reduce the risk of metabolic syndrome. However, the active component remains unclear. Recently, we identified bioactive peptides [leucine-arginine-proline (LRP) and leucine-glutamine‑proline (LQP)] from wheat bran autolytic hydrolysate. The present study aimed to investigate the effects of LRP and LQP on non-alcoholic steatohepatitis (NASH) in a mouse model. We also evaluated the effects of these peptides on oxidative stress and on the AMP-activated protein kinase (AMPK) signaling pathway, two major pathogenic factors of NASH. Seven‑week-old male C57BL/6 mice were fed a high-fat diet for 10 weeks and administered water supplemented with 0.05% LRP, 0.20% LRP, 0.05% LQP, or 0.20% LQP (each n=5) or distilled water (control; n=5) ad libitum. Oxidative stress was evaluated by measuring the serum levels of diacron reactive oxygen metabolite (d-ROM) and biological antioxidant potential (BAP). Hepatic expression of phosphorylated AMPK and phosphorylated acetyl-CoA carboxylase (ACC) were evaluated by immunoblotting. The result showed that non‑alcoholic fatty liver disease activity score was significantly decreased in all types of treatment. Serum d-ROM levels were significantly decreased in the 0.20% LRP group, but not in the 0.05% LRP, 0.05% LQP, and 0.20% LQP groups. Serum BAP levels were significantly increased in the 0.05% LRP and 0.20% LRP groups, but not in the 0.05% LQP and 0.20% LQP groups. Immunoblotting analysis revealed that the expression of phospho-AMPK was increased whereas that of phospho-ACC was decreased in the 0.20% LQP group. In conclusion, we demonstrated that both LRP and LQP alleviated the severity of NASH in a high-fat diet-induced NASH mouse model. In addition, we showed that LRP and LQP modulated oxidative stress and upregulated AMPK/ACC, respectively. Thus, LRP and LQP may constitute clinically applicable therapeutic agents for NASH.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Kawaguchi
authors.affiliation: Asakura Medical Association Hospital, Asakura, Japan.
authors.forename: Takato
authors.initials: T
authors.lastname: Ueno
authors.affiliation: NARO Western Region Agricultural Research Center, Kagawa, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Nogata
authors.affiliation: Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Hayakawa
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Koga
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Torimura
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism*; D000597:Amino Acids, Branched-Chain / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001835:Body Weight; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014908:Triticum / Q000737:chemistry
chemical_list: D000597:Amino Acids, Branched-Chain; D000975:Antioxidants; D010455:Peptides; D017382:Reactive Oxygen Species; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase