title: L-carnitine prevents metabolic steatohepatitis in obese diabetic KK-Aymice.
abstract: OBJECTIVE
  Pharmacological treatment for metabolic syndrome-related non-alcoholic steatohepatitis has not been established. We investigated the effect of L-carnitine, an essential substance for β-oxidation, on metabolic steatohepatitis in mice.
  
  
  METHODS
  Male KK-Aymice were fed a high-fat diet (HFD) for 8 weeks, with supplementation of L-carnitine (1.25 mg/mL) in drinking water for the latter 4 weeks.
  
  
  RESULTS
  Serum total carnitine levels were decreased following HFD feeding, whereas the levels were reversed almost completely by L-carnitine supplementation. In mice given L-carnitine, exacerbation of hepatic steatosis and hepatocyte apoptosis was markedly prevented even though HFD feeding was continued. Body weight gain, as well as hyperlipidemia, hyperglycemia, and hyperinsulinemia, following HFD feeding were also significantly prevented in mice given L-carnitine. High-fat diet feeding elevated hepatic expression levels of carnitine palmitoyltransferase 1A mRNA; however, production of β-hydroxybutyrate in the liver was not affected by HFD alone. In contrast, L-carnitine treatment significantly increased hepatic β-hydroxybutyrate contents in HFD-fed mice. L-carnitine also blunted HFD induction in sterol regulatory element binding protein-1c mRNA in the liver. Furthermore, L-carnitine inhibited HFD-induced serine phosphorylation of insulin receptor substrate-1 in the liver. L-carnitine decreased hepatic free fatty acid content in 1 week, with morphological improvement of swollen mitochondria in hepatocytes, and increases in hepatic adenosine 5'-triphosphate content.
  
  
  CONCLUSIONS
  L-carnitine ameliorates steatohepatitis in KK-Aymice fed an HFD, most likely through facilitating mitochondrial β-oxidation, normalizing insulin signals, and inhibiting de novo lipogenesis in the liver. It is therefore postulated that supplementation of L-carnitine is a promising approach for prevention and treatment of metabolic syndrome-related non-alcoholic steatohepatitis.
authors.affiliation: Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kon
authors.affiliation: Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Ikejima
authors.affiliation: Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Morinaga
authors.affiliation: Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kusama
authors.affiliation: Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Arai
authors.affiliation: Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Aoyama
authors.affiliation: Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Uchiyama
authors.affiliation: Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Shunhei
authors.initials: S
authors.lastname: Yamashina
authors.affiliation: Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Sumio
authors.initials: S
authors.lastname: Watanabe
keywords: free fatty acid; insulin signal; metabolic syndrome; non-alcoholic steatohepatitis (NASH); β-oxidation