{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T18:00:29Z","timestamp":1778349629665,"version":"3.51.4"},"reference-count":42,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","license":[{"start":{"date-parts":[[2018,10,1]],"date-time":"2018-10-01T00:00:00Z","timestamp":1538352000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hepatol Commun"],"published-print":{"date-parts":[[2018,12]]},"abstract":"<jats:p>With the epidemic of obesity, nonalcoholic fatty liver disease (NAFLD) has become the most common pediatric liver disease. The influence of a perinatal obesity\u2010inducing 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\u2010Chow, pChow\u2010FFC, pFFC\u2010Chow, and pFFC\u2010FFC. Mice were sacrificed at 10 weeks of age. We examined the whole\u2010liver transcriptome by RNA sequencing (RNA\u2010seq) and whole\u2010liver genome methylation by reduced representation bisulfite sequencing (RRBS). Our results indicated that the pFFC\u2010FFC 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\u2010FFC mice versus the pChow\u2010FFC 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\u2010Chow 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.<jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: 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.<\/jats:p>","DOI":"10.1002\/hep4.1265","type":"journal-article","created":{"date-parts":[[2018,10,2]],"date-time":"2018-10-02T00:13:24Z","timestamp":1538439204000},"page":"1493-1512","source":"Crossref","is-referenced-by-count":30,"title":["Perinatal Nutritional Reprogramming of the Epigenome Promotes Subsequent Development of Nonalcoholic Steatohepatitis"],"prefix":"10.1097","volume":"2","author":[{"given":"Luz Helena","family":"Gutierrez Sanchez","sequence":"first","affiliation":[{"name":"Division of Pediatric Gastroenterology and Hepatology,Mayo Clinic,Rochester,MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyoko","family":"Tomita","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Mayo Clinic,Rochester,MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qianqian","family":"Guo","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Mayo Clinic,Rochester,MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kunimaro","family":"Furuta","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Mayo Clinic,Rochester,MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Husam","family":"Alhuwaish","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Mayo Clinic,Rochester,MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0494-0924","authenticated-orcid":false,"given":"Petra","family":"Hirsova","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Mayo Clinic,Rochester,MN"},{"name":"Institute of Clinical Biochemistry and Diagnostics,University Hospital Hradec Kralove,Hradec Kralove,Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saurabh","family":"Baheti","sequence":"additional","affiliation":[{"name":"Division of Biomedical Statistics and Informatics,Mayo Clinic,Rochester,MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bonnie","family":"Alver","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics,Mayo Clinic,Rochester,MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2829-4237","authenticated-orcid":false,"given":"Ryan","family":"Hlady","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics,Mayo Clinic,Rochester,MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keith D.","family":"Robertson","sequence":"additional","affiliation":[{"name":"Department of Molecular 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