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Perinatal Nutritional Reprogramming of the Epigenome Promotes Subsequent Development of Nonalcoholic Steatohepatitis.

ABSTRACT: 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.

SUBMITTER: Gutierrez Sanchez LH

PROVIDER: S-EPMC6287484 | biostudies-other | 2018 Dec

REPOSITORIES: biostudies-other

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Perinatal Nutritional Reprogramming of the Epigenome Promotes Subsequent Development of Nonalcoholic Steatohepatitis.

Gutierrez Sanchez Luz Helena LH Tomita Kyoko K Guo Qianqian Q Furuta Kunimaro K Alhuwaish Husam H Hirsova Petra P Baheti Saurabh S Alver Bonnie B Hlady Ryan R Robertson Keith D KD Ibrahim Samar H SH

Hepatology communications 20181001 12

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, generati ...[more]

PMID: 30556038

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Project description:Methods: To better understand the role of OX40 in the regulation of monocyte activation and polarization, OX40/Fc- or control IgG-treated liver monocytes were compared in a transcriptome sequencing study. Total RNA was isolated from FACS-separated hepatic monocytes. Transcriptome sequencing libraries were generated using NEBNext® Ultra™ RNA Library Prep Kit for Illumina® (NEB, USA) following manufacturer’s recommendations and sequenced on an Illumina Hiseq platform (Illumina, San Diego, CA). Sequences were aligned to the reference genome with TopHat and processed with Cufflinks, which quantifies each transcript in each sample using reference annotations produced bythe University of California Santa Cruz UCSC. Differentially expressed genes with a fold change of >=2.0 and padj < 0.05 between OX40 treated and control monocytes were submitted to GO and KEGG enrichment analysis, which uses unbiased methods to assess pathway enrichment. Results: Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that upregulated genes from OX40-stimulated monocytes are involved in inflammatory response; cytokine production regulation; lipid, cytokine and bacteria responses; innate immune response; enhanced cellular response to cytokines and the cytokine-cytokine receptor interaction; and the phagosome and chemokine signaling pathway, among others. Compared to control monocytes, OX40/Fc-treated monocytes exhibited upregulated levels of cytokines (Tnf, Il1a, Il1b, Il6 and Il12a), cytokine receptors (Il1rl1, Il2r, Il18r and Il23r), chemokines (Ccl3, Ccl4, Ccl22, Cxcl1, Cxcl2, Cxcl10 and Cx3cl1), chemokine receptors ( Ccrl2, Cxcr5 and Cxcr6) and antigen processing and presentation molecules (Cd40, Cd80, Cd86, Tlr1, Tlr2, and Ox40l). The coordinated action of various inflammatory modulators, signaling molecules, and transcription factors, including Nlrp3, Tank, Jak2, Stat5a, Hif1a, Nos2, Socs3, Mir155hg and Pparg, was determined to be involved in the OX40 regulation of monocyte M1 polarization. MyD88, Irf3, Irf5, Stat1, Nod1 and Nod2 may not be involved in OX40-triggered monocyte M1 polarization.

Dataset Information

Perinatal Nutritional Reprogramming of the Epigenome Promotes Subsequent Development of Nonalcoholic Steatohepatitis.

Publications

Perinatal Nutritional Reprogramming of the Epigenome Promotes Subsequent Development of Nonalcoholic Steatohepatitis.

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