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Mechanism of the development of nonalcoholic steatohepatitis after pancreaticoduodenectomy.
BBA Clin. 2015 Jun; 3:168-74.BC

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 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.

Authors+Show Affiliations

Department of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan.Department of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan ; Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Matsumoto, Japan.Department of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan.Department of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan.Department of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan.Department of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan.Digestive Disease Center, Showa Inan General Hospital, Komagane, Japan.Department of Gastroenterology, Iida Municipal Hospital, Iida, Japan.Department of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan.Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan.Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States.Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Matsumoto, Japan.Department of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

26674248

Citation

Nagaya, Tadanobu, et al. "Mechanism of the Development of Nonalcoholic Steatohepatitis After Pancreaticoduodenectomy." BBA Clinical, vol. 3, 2015, pp. 168-74.
Nagaya T, Tanaka N, Kimura T, et al. Mechanism of the development of nonalcoholic steatohepatitis after pancreaticoduodenectomy. BBA Clin. 2015;3:168-74.
Nagaya, T., Tanaka, N., Kimura, T., Kitabatake, H., Fujimori, N., Komatsu, M., Horiuchi, A., Yamaura, T., Umemura, T., Sano, K., Gonzalez, F. J., Aoyama, T., & Tanaka, E. (2015). Mechanism of the development of nonalcoholic steatohepatitis after pancreaticoduodenectomy. BBA Clinical, 3, 168-74. https://doi.org/10.1016/j.bbacli.2015.02.001
Nagaya T, et al. Mechanism of the Development of Nonalcoholic Steatohepatitis After Pancreaticoduodenectomy. BBA Clin. 2015;3:168-74. PubMed PMID: 26674248.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mechanism of the development of nonalcoholic steatohepatitis after pancreaticoduodenectomy. AU - Nagaya,Tadanobu, AU - Tanaka,Naoki, AU - Kimura,Takefumi, AU - Kitabatake,Hiroyuki, AU - Fujimori,Naoyuki, AU - Komatsu,Michiharu, AU - Horiuchi,Akira, AU - Yamaura,Takahiro, AU - Umemura,Takeji, AU - Sano,Kenji, AU - Gonzalez,Frank J, AU - Aoyama,Toshifumi, AU - Tanaka,Eiji, Y1 - 2015/02/19/ PY - 2014/12/13/received PY - 2015/02/05/revised PY - 2015/02/10/accepted PY - 2015/12/18/entrez PY - 2015/12/18/pubmed PY - 2015/12/18/medline KW - ACACA, acetyl-CoA carboxylase α KW - ACACB, acetyl-CoA carboxylase β KW - ACADM, medium-chain acyl-CoA dehydrogenase KW - ACOX1, acyl-CoA oxidase 1 KW - ALT, alanine aminotransferase KW - AST, aspartate aminotransferase KW - ApoB, apolipoprotein B KW - BMI, body mass index KW - CAT, catalase KW - CPT1A, carnitine palmitoyl-CoA transferase 1α KW - CT, computed tomography KW - CYBB, cytochrome b-245 β polypeptide KW - CYP, cytochrome P450 KW - CoA, coenzyme A KW - DGAT, diacylglycerol acyltransferase KW - FA, fatty acid KW - FABP, fatty acid-binding protein KW - FASN, fatty acid synthase KW - Fatty acid KW - HADHA, hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase α KW - HBV, hepatitis B virus KW - HCV, hepatitis C virus KW - HOMA-IR, homeostasis model assessment for insulin resistance KW - LPS, lipopolysaccharide KW - LXR, liver X receptor KW - MCD, methionine- and choline-deficient diet KW - MTTP, microsomal triglyceride transfer protein KW - MYD88, myeloid differentiation primary response 88 KW - MyD88 KW - NAFLD, nonalcoholic fatty liver disease KW - NAS, NAFLD activity score KW - NASH KW - NASH, nonalcoholic steatohepatitis KW - PD, pancreaticoduodenectomy KW - PPAR, peroxisome proliferator-activated receptor KW - PPARGC, PPARγ co-activator KW - Pancreaticoduodenectomy KW - ROS, reactive oxygen species KW - RXR, retinoid X receptor KW - SCD, stearoyl-CoA desaturase KW - SOD, superoxide dismutase KW - SREBF1, sterol regulatory element-binding transcription factor 1 KW - TG, triglyceride KW - TGFB1, transforming growth factor β1 KW - TLR, Toll-like receptor KW - TNF, tumor necrosis factor α KW - US, ultrasonography KW - VLDL KW - VLDL, very-low-density lipoprotein KW - qPCR, quantitative polymerase chain reaction KW - γGT, gamma-glutamyltransferase SP - 168 EP - 74 JF - BBA clinical JO - BBA Clin VL - 3 N2 - 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. SN - 2214-6474 UR - https://www.unboundmedicine.com/medline/citation/26674248/Mechanism_of_the_development_of_nonalcoholic_steatohepatitis_after_pancreaticoduodenectomy_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S2214-6474(15)00008-2 DB - PRIME DP - Unbound Medicine ER -
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