Mechanism of the development of nonalcoholic steatohepatitis after pancreaticoduodenectomy

Tadanobu Nagaya, Naoki Tanaka, Takefumi Kimura, Hiroyuki Kitabatake, Naoyuki Fujimori, Michiharu Komatsu, Akira Horiuchi, Takahiro Yamaura, Takeji Umemura, Kenji Sano, Frank J Gonzalez, Toshifumi Aoyama, Eiji Tanaka
BBA Clinical 2015, 3: 168-74

BACKGROUND AND AIM: 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.

GENERAL SIGNIFICANCE: These results provide a basis for understanding the pathogenesis of NAFLD/NASH following PD.

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