title: Glucagon-like peptide-1 analogue prevents nonalcoholic steatohepatitis in non-obese mice.
abstract: OBJECTIVE
  To investigate whether a glucagon-like peptide-1 (GLP-1) analogue inhibits nonalcoholic steatohepatitis (NASH), which is being increasingly recognized in Asia, in non-obese mice.
  
  
  METHODS
  A methionine-choline-deficient diet (MCD) along with exendin-4 (20 μg/kg per day, ip), a GLP-1 analogue, or saline was administered to male db/db mice (non-obese NASH model). Four or eight weeks after commencement of the diet, the mice were sacrificed and their livers were excised. The excised livers were examined by histochemistry for evidence of hepatic steatosis and inflammation. Hepatic triglyceride (TG) and free fatty acid (FFA) content was measured, and the expression of hepatic fat metabolism- and inflammation-related genes was evaluated. Oxidative stress-related parameters and macrophage recruitment were also examined using immunohistochemistry.
  
  
  RESULTS
  Four weeks of MCD feeding induced hepatic steatosis and inflammation and increased the hepatic TG and FFA content. The expression of fatty acid transport protein 4 (FATP4), a hepatic FFA influx-related gene; macrophage recruitment; and the level of malondialdehyde (MDA), an oxidative stress marker, were significantly augmented by a 4-wk MCD. The levels of hepatic sterol regulatory element-binding protein-1c (SREBP-1c) mRNA (lipogenesis-related gene) and acyl-coenzyme A oxidase 1 (ACOX1) mRNA (β-oxidation-related gene) had decreased at 4 wk and further decreased at 8 wk. However, the level of microsomal triglyceride transfer protein mRNA (a lipid excretion-related gene) remained unchanged. The administration of exendin-4 significantly attenuated the MCD-induced increase in hepatic steatosis, hepatic TG and FFA content, and FATP4 expression as well as the MCD-induced augmentation of hepatic inflammation, macrophage recruitment, and MDA levels. Additionally, it further decreased the hepatic SREBP-1c level and alleviated the MCD-mediated inhibition of the ACOX1 mRNA level.
  
  
  CONCLUSIONS
  These results suggest that GLP-1 inhibits hepatic steatosis and inflammation through the inhibition of hepatic FFA influx and oxidative stress in a non-obese NASH model.
authors.affiliation: Takaya Yamamoto, Yukiomi Nakade, Taeko Yamauchi, Yuji Kobayashi, Norimitsu Ishii, Tomohiko Ohashi, Kiyoaki Ito, Ken Sato, Yoshitaka Fukuzawa, Masashi Yoneda, Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi 480-1195, Japan.
authors.forename: Takaya
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Takaya Yamamoto, Yukiomi Nakade, Taeko Yamauchi, Yuji Kobayashi, Norimitsu Ishii, Tomohiko Ohashi, Kiyoaki Ito, Ken Sato, Yoshitaka Fukuzawa, Masashi Yoneda, Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi 480-1195, Japan.
authors.forename: Yukiomi
authors.initials: Y
authors.lastname: Nakade
authors.affiliation: Takaya Yamamoto, Yukiomi Nakade, Taeko Yamauchi, Yuji Kobayashi, Norimitsu Ishii, Tomohiko Ohashi, Kiyoaki Ito, Ken Sato, Yoshitaka Fukuzawa, Masashi Yoneda, Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi 480-1195, Japan.
authors.forename: Taeko
authors.initials: T
authors.lastname: Yamauchi
authors.affiliation: Takaya Yamamoto, Yukiomi Nakade, Taeko Yamauchi, Yuji Kobayashi, Norimitsu Ishii, Tomohiko Ohashi, Kiyoaki Ito, Ken Sato, Yoshitaka Fukuzawa, Masashi Yoneda, Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi 480-1195, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Takaya Yamamoto, Yukiomi Nakade, Taeko Yamauchi, Yuji Kobayashi, Norimitsu Ishii, Tomohiko Ohashi, Kiyoaki Ito, Ken Sato, Yoshitaka Fukuzawa, Masashi Yoneda, Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi 480-1195, Japan.
authors.forename: Norimitsu
authors.initials: N
authors.lastname: Ishii
authors.affiliation: Takaya Yamamoto, Yukiomi Nakade, Taeko Yamauchi, Yuji Kobayashi, Norimitsu Ishii, Tomohiko Ohashi, Kiyoaki Ito, Ken Sato, Yoshitaka Fukuzawa, Masashi Yoneda, Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi 480-1195, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ohashi
authors.affiliation: Takaya Yamamoto, Yukiomi Nakade, Taeko Yamauchi, Yuji Kobayashi, Norimitsu Ishii, Tomohiko Ohashi, Kiyoaki Ito, Ken Sato, Yoshitaka Fukuzawa, Masashi Yoneda, Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi 480-1195, Japan.
authors.forename: Kiyoaki
authors.initials: K
authors.lastname: Ito
authors.affiliation: Takaya Yamamoto, Yukiomi Nakade, Taeko Yamauchi, Yuji Kobayashi, Norimitsu Ishii, Tomohiko Ohashi, Kiyoaki Ito, Ken Sato, Yoshitaka Fukuzawa, Masashi Yoneda, Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi 480-1195, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Sato
authors.affiliation: Takaya Yamamoto, Yukiomi Nakade, Taeko Yamauchi, Yuji Kobayashi, Norimitsu Ishii, Tomohiko Ohashi, Kiyoaki Ito, Ken Sato, Yoshitaka Fukuzawa, Masashi Yoneda, Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi 480-1195, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Fukuzawa
authors.affiliation: Takaya Yamamoto, Yukiomi Nakade, Taeko Yamauchi, Yuji Kobayashi, Norimitsu Ishii, Tomohiko Ohashi, Kiyoaki Ito, Ken Sato, Yoshitaka Fukuzawa, Masashi Yoneda, Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi 480-1195, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Yoneda
mesh_terms: D042962:Acyl-CoA Oxidase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D004195:Disease Models, Animal; D000077270:Exenatide; D050612:Fatty Acid Transport Proteins / Q000235:genetics / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005786:Gene Expression Regulation; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D016688:Mice, Inbred NOD; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018384:Oxidative Stress / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism; D014688:Venoms / Q000494:pharmacology*
chemical_list: D015415:Biomarkers; D050612:Fatty Acid Transport Proteins; D005230:Fatty Acids, Nonesterified; D018836:Inflammation Mediators; D010455:Peptides; C493572:Slc27a4 protein, mouse; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D042962:Acyl-CoA Oxidase
keywords: Free fatty acid; Glucagon like peptide-1; Kupffer cells; Nonalcoholic steatohepatitis; Oxidative stress