Mechanism of the development of nonalcoholic steatohepatitis after pancreaticoduodenectomy

• The mechanism of NASH development after pancreaticoduodenectomy (PD) was unclear.
• The gene expression involved in fatty acid uptake and lipogenesis was increased.
• PPARγ and its target genes were up-regulated in post-PD NASH livers.
• Impaired triglyceride excretion from the liver was suggested in post-PD NASH.
• This study proposes possible mechanisms of steatogenesis after PD.

Background and aimIt 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.MethodsThe 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.ResultsThe 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.ConclusionsEnhanced 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 significanceThese results provide a basis for understanding the pathogenesis of NAFLD/NASH following PD.