Dataset Information

Mechanism of the development of nonalcoholic steatohepatitis after pancreaticoduodenectomy.

ABSTRACT:

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 ?, diacylglycerol acyltransferase 2, and peroxisome proliferator-activated receptor (PPAR) ? 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 PPAR?, 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.

SUBMITTER: Nagaya T

PROVIDER: S-EPMC4661550 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Publications

Mechanism of the development of nonalcoholic steatohepatitis after pancreaticoduodenectomy.

Nagaya Tadanobu T Tanaka Naoki N Kimura Takefumi T Kitabatake Hiroyuki H Fujimori Naoyuki N Komatsu Michiharu M Horiuchi Akira A Yamaura Takahiro T Umemura Takeji T Sano Kenji K Gonzalez Frank J FJ Aoyama Toshifumi T Tanaka Eiji E

BBA clinical 20150219

<h4>Background and aim</h4>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.<h4>Methods</h4>The expression of genes related to fatty acid/triglyceride (FA/TG) metabolism and inflammatory signaling was examined using liver samp ...[more]

PMID: 26674248

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Project description:With the epidemic of obesity, nonalcoholic fatty liver disease (NAFLD) has become the most common pediatric liver disease. The influence of a perinatal obesity-inducing diet (OID) on the development and progression of NAFLD in offspring is important but incompletely studied. Hence, we fed breeding pairs of C57BL/6J mice during gestation and lactation (perinatally) either chow or an OID rich in fat, fructose, and cholesterol (FFC). The offspring were weaned to either chow or an FFC diet, generating four groups: perinatal (p)Chow-Chow, pChow-FFC, pFFC-Chow, and pFFC-FFC. Mice were sacrificed at 10 weeks of age. We examined the whole-liver transcriptome by RNA sequencing (RNA-seq) and whole-liver genome methylation by reduced representation bisulfite sequencing (RRBS). Our results indicated that the pFFC-FFC mice had a significant increase in hepatic steatosis, injury, inflammation, and fibrosis, as assessed histologically and biochemically. We identified 189 genes that were differentially expressed and methylated in the pFFC-FFC mice versus the pChow-FFC mice. Gene set enrichment analysis identified hepatic fibrosis/hepatic stellate cell activation as the top canonical pathway, suggesting that the differential DNA methylation events in the mice exposed to the FFC diet perinatally were associated with a profibrogenic transcriptome. To verify that this finding was consistent with perinatal nutritional reprogramming of the methylome, we exposed pFFC-Chow mice to an FFC diet in adulthood. These mice developed significant hepatic steatosis, injury, inflammation, and more importantly fibrosis when compared to the appropriate controls. Conclusion: Perinatal exposure to an OID primes the immature liver for an accentuated fibrosing nonalcoholic steatohepatitis (NASH) phenotype, likely through nutritional reprogramming of the offspring methylome. These data have potential clinical implications for monitoring children of obese mothers and risk stratification of children with NAFLD.

Dataset Information

Mechanism of the development of nonalcoholic steatohepatitis after pancreaticoduodenectomy.

Background and aim

Methods

Results

Conclusions

General significance

Publications

Mechanism of the development of nonalcoholic steatohepatitis after pancreaticoduodenectomy.

Similar Datasets

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