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.
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.