title: Mechanism of the development of nonalcoholic steatohepatitis after pancreaticoduodenectomy.
abstract: OBJECTIVE
  It is recognized that nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), may develop after pancreaticoduodenectomy (PD). However, the mechanism of NASH development remains unclear. This study aimed to examine the changes in gene expression associated with NASH occurrence following PD.
  
  
  METHODS
  The expression of genes related to fatty acid/triglyceride (FA/TG) metabolism and inflammatory signaling was examined using liver samples obtained from 7 post-PD NASH patients and compared with 6 healthy individuals and 32 conventional NASH patients.
  
  
  RESULTS
  The livers of post-PD NASH patients demonstrated significant up-regulation of the genes encoding CD36, FA-binding proteins 1 and 4, acetyl-coenzyme A carboxylase α, diacylglycerol acyltransferase 2, and peroxisome proliferator-activated receptor (PPAR) γ compared with normal and conventional NASH livers. Although serum apolipoprotein B (ApoB) and TG were decreased in post-PD NASH patients, the mRNAs of ApoB and microsomal TG transfer protein were robustly increased, indicating impaired TG export from the liver as very-low-density lipoprotein (VLDL). Additionally, elevated mRNA levels of myeloid differentiation primary response 88 and superoxide dismutases in post-PD NASH livers suggested significant activation of innate immune response and augmentation of oxidative stress generation.
  
  
  CONCLUSIONS
  Enhanced FA uptake into hepatocytes and lipogenesis, up-regulation of PPARγ, and disruption of VLDL excretion into the circulation are possible mechanisms of steatogenesis after PD.
  
  
  CONCLUSIONS
  These results provide a basis for understanding the pathogenesis of NAFLD/NASH following PD.
authors.affiliation: Department of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Tadanobu
authors.initials: T
authors.lastname: Nagaya
authors.affiliation: Department of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan ; Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Tanaka
authors.affiliation: Department of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Takefumi
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Department of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kitabatake
authors.affiliation: Department of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Fujimori
authors.affiliation: Department of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Michiharu
authors.initials: M
authors.lastname: Komatsu
authors.affiliation: Digestive Disease Center, Showa Inan General Hospital, Komagane, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Horiuchi
authors.affiliation: Department of Gastroenterology, Iida Municipal Hospital, Iida, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamaura
authors.affiliation: Department of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Takeji
authors.initials: T
authors.lastname: Umemura
authors.affiliation: Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Sano
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Aoyama
authors.affiliation: Department of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Tanaka
keywords: ACACA, acetyl-CoA carboxylase α; ACACB, acetyl-CoA carboxylase β; ACADM, medium-chain acyl-CoA dehydrogenase; ACOX1, acyl-CoA oxidase 1; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ApoB, apolipoprotein B; BMI, body mass index; CAT, catalase; CPT1A, carnitine palmitoyl-CoA transferase 1α; CT, computed tomography; CYBB, cytochrome b-245 β polypeptide; CYP, cytochrome P450; CoA, coenzyme A; DGAT, diacylglycerol acyltransferase; FA, fatty acid; FABP, fatty acid-binding protein; FASN, fatty acid synthase; Fatty acid; HADHA, hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase α; HBV, hepatitis B virus; HCV, hepatitis C virus; HOMA-IR, homeostasis model assessment for insulin resistance; LPS, lipopolysaccharide; LXR, liver X receptor; MCD, methionine- and choline-deficient diet; MTTP, microsomal triglyceride transfer protein; MYD88, myeloid differentiation primary response 88; MyD88; NAFLD, nonalcoholic fatty liver disease; NAS, NAFLD activity score; NASH; NASH, nonalcoholic steatohepatitis; PD, pancreaticoduodenectomy; PPAR, peroxisome proliferator-activated receptor; PPARGC, PPARγ co-activator; Pancreaticoduodenectomy; ROS, reactive oxygen species; RXR, retinoid X receptor; SCD, stearoyl-CoA desaturase; SOD, superoxide dismutase; SREBF1, sterol regulatory element-binding transcription factor 1; TG, triglyceride; TGFB1, transforming growth factor β1; TLR, Toll-like receptor; TNF, tumor necrosis factor α; US, ultrasonography; VLDL; VLDL, very-low-density lipoprotein; qPCR, quantitative polymerase chain reaction; γGT, gamma-glutamyltransferase