title: Augmented hepatic Toll-like receptors by fatty acids trigger the pro-inflammatory state of non-alcoholic fatty liver disease in mice.
abstract: OBJECTIVE
  There is considerable evidence that intestinal microbiota are involved in the development of metabolic syndromes and, consequently, with the development of non-alcoholic fatty liver disease (NAFLD). Toll-like receptors (TLRs) are essential for the recognition of microbiota. However, the induction mechanism of TLR signals through the gut-liver axis for triggering the development of non-alcoholic steatohepatitis (NASH) or NAFLD remains unclear. In this study, we investigated the role of palmitic acid (PA) in triggering the development of a pro-inflammatory state of NAFLD.
  
  
  METHODS
  Non-alcoholic fatty liver disease was induced in mice fed a high fat diet (HFD). The mice were killed and the expression of TLRs, tumor necrosis factor (TNF), interleukin (IL)-1β, and phospho-interleukin-1 receptor-associated kinase 1 in the liver and small intestine were assessed. In addition, primary hepatocytes and Kupffer cells were treated with PA, and the direct effects of PA on TLRs induction by these cells were evaluated.
  
  
  RESULTS
  The expression of inflammatory cytokines such as TNF, IL-1β, and TLR-2, -4, -5, and -9 was increased in the liver, but decreased in the small intestine of HFD-fed mice in vivo. In addition, the expression of TLRs in primary hepatocytes and Kupffer cells was increased by treatment with PA.
  
  
  CONCLUSIONS
  In the development of the pro-inflammatory state of NAFLD, PA triggers the expression of TLRs, which contribute to the induction of inflammatory cytokines through TLR signals by intestinal microbiota.
authors.affiliation: Department of Medicine, Division of Gastroenterology and Hematology/Oncology, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Sawada
authors.forename: Takaaki
authors.initials: T
authors.lastname: Ohtake
authors.forename: Takumu
authors.initials: T
authors.lastname: Hasebe
authors.forename: Masami
authors.initials: M
authors.lastname: Abe
authors.forename: Hiroki
authors.initials: H
authors.lastname: Tanaka
authors.forename: Katsuya
authors.initials: K
authors.lastname: Ikuta
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Mikihiro
authors.initials: M
authors.lastname: Fujiya
authors.forename: Chitomi
authors.initials: C
authors.lastname: Hasebe
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kohgo
keywords: Toll-like receptor; fatty acids; gut-liver axis; non-alcoholic fatty liver disease; pro-inflammatory state