title: Branched-chain amino acids reduce hepatic iron accumulation and oxidative stress in hepatitis C virus polyprotein-expressing mice.
abstract: OBJECTIVE
  Branched-chain amino acids (BCAA) reduce the incidence of hepatocellular carcinoma (HCC) in patients with cirrhosis. However, the mechanisms that underlie these effects remain unknown. Previously, we reported that oxidative stress in male transgenic mice that expressed hepatitis C virus polyprotein (HCVTgM) caused hepatic iron accumulation by reducing hepcidin transcription, thereby leading to HCC development. This study investigated whether long-term treatment with BCAA reduced hepatic iron accumulation and oxidative stress in iron-overloaded HCVTgM and in patients with HCV-related advanced fibrosis.
  
  
  METHODS
  Male HCVTgM were fed an excess-iron diet that comprised either casein or 3.0% BCAA, or a control diet, for 6 months.
  
  
  RESULTS
  For HCVTgM, BCAA supplementation increased the serum hepcidin-25 levels and antioxidant status [ratio of biological antioxidant potential (BAP) relative to derivatives of reactive oxygen metabolites (dROM)], decreased the hepatic iron contents, attenuated reactive oxygen species generation, and restored mitochondrial superoxide dismutase expression and mitochondrial complex I activity in the liver compared with mice fed the control diet. After 48 weeks of BCAA supplementation in patients with HCV-related advanced fibrosis, BAP/dROM and serum hepcidin-25 increased and serum ferritin decreased compared with the pretreatment levels.
  
  
  CONCLUSIONS
  BCAA supplementation reduced oxidative stress by restoring mitochondrial function and improved iron metabolism by increasing hepcidin-25 in both iron-overloaded HCVTgM and patients with HCV-related advanced fibrosis. These activities of BCAA may partially account for their inhibitory effects on HCC development in cirrhosis patients.
authors.affiliation: Department of Hepatology and Pancreatology, Kawasaki Medical School, Okayama, Japan; The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine (NCGM), Chiba, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Korenaga
authors.forename: Sohji
authors.initials: S
authors.lastname: Nishina
authors.forename: Keiko
authors.initials: K
authors.lastname: Korenaga
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Tomiyama
authors.forename: Naoko
authors.initials: N
authors.lastname: Yoshioka
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hara
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Shimonaka
authors.forename: Keisuke
authors.initials: K
authors.lastname: Hino
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000597:Amino Acids, Branched-Chain / Q000008:administration & dosage*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D004044:Dietary Proteins / Q000008:administration & dosage*; D004195:Disease Models, Animal; D005260:Female; D005293:Ferritins / Q000097:blood; D016174:Hepacivirus / Q000235:genetics / Q000378:metabolism*; D006526:Hepatitis C / Q000097:blood / Q000178:diet therapy* / Q000235:genetics / Q000378:metabolism; D064451:Hepcidins / Q000097:blood; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007564:Japan; D008099:Liver / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000097:blood / Q000178:diet therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008822:Mice, Transgenic; D018384:Oxidative Stress; D020815:Polyproteins / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000097:blood; D013997:Time Factors; D016896:Treatment Outcome; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000597:Amino Acids, Branched-Chain; D000975:Antioxidants; D015415:Biomarkers; D004044:Dietary Proteins; D064451:Hepcidins; D020815:Polyproteins; D017382:Reactive Oxygen Species; D014764:Viral Proteins; C545475:hepcidin 25, human; D005293:Ferritins; D007501:Iron
keywords: hepatic mitochondrial dysfunction; hepatitis C virus; hepcidin-25; iron metabolic disorder; reactive oxygen species