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Poor vitamin C (VitC) status may affect MASH progression and often co-occurs with high-fat diets and related metabolic imbalances. As a regulator of DNA methylation, poor VitC status may further contribute to MASH by regulating gene expression This study investigated guinea pigs\u2014a species that, like humans, depends on vitC in the diet\u2014as a model of pediatric MASH, examining the effects of poor VitC status on MASH hallmarks and global DNA methylation levels. Methods: Sixty-two juvenile guinea pigs were exposed to a high-fat diet for 16 weeks. Results: Juvenile guinea pigs exhibited hepatic histopathology representative of pediatric MASH, confirmed by portal inflammation and fibrosis. Consistent with pediatric MASH, juvenile guinea pigs displayed increased lobular and portal inflammation (p &lt; 0.05 and p &lt; 0.0001, respectively) but less steatosis (p &lt; 0.001) compared to adults. Compared to the controls, the guinea pigs deprived in VitC showed lower body weight (p &lt; 0.01), higher expression of hepatic inflammatory genes (p &lt; 0.05), and a lower global hydroxymethylcytosine to methylcytosine ratio in the high-fat groups (p &lt; 0.05). Conclusions: Our study validates guinea pigs as a model of pediatric MASH and suggests that VitC contributes to an altered gene expression signature through the regulation of DNA hydroxymethylation. We postulate that nutritional co-deficiencies in MASH, such as low VitC, may accelerate disease progression and deserve further attention.<\/jats:p>","DOI":"10.3390\/nu17020291","type":"journal-article","created":{"date-parts":[[2025,1,15]],"date-time":"2025-01-15T04:42:08Z","timestamp":1736916128000},"page":"291","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Guinea Pig Model of Pediatric Metabolic Dysfunction-Associated Steatohepatitis: Poor Vitamin C Status May Advance Disease"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2852-2882","authenticated-orcid":false,"given":"Kamilla","family":"Pedersen","sequence":"first","affiliation":[{"name":"Section of Preclinical Disease Biology, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2547-5403","authenticated-orcid":false,"given":"Ankita","family":"Poojari","sequence":"additional","affiliation":[{"name":"Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, CA 95211, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone Frederikke","family":"Colberg","sequence":"additional","affiliation":[{"name":"Section of Preclinical Disease Biology, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stine Marguerite","family":"Mechernsee","sequence":"additional","affiliation":[{"name":"Section of Preclinical Disease Biology, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo Fr\u00f8kj\u00e6r","family":"Iversen","sequence":"additional","affiliation":[{"name":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romain","family":"Barr\u00e8s","sequence":"additional","affiliation":[{"name":"Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen, Denmark"},{"name":"Institut de Pharmacologie Mol\u00e9culaire et Cellulaire, CNRS and Universit\u00e9 de Nice C\u00f4te d\u2019Azur, 06560 Valbonne, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6514-8407","authenticated-orcid":false,"given":"Jens","family":"Lykkesfeldt","sequence":"additional","affiliation":[{"name":"Section of Preclinical Disease Biology, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5574-5742","authenticated-orcid":false,"given":"Pernille","family":"Tveden-Nyborg","sequence":"additional","affiliation":[{"name":"Section of Preclinical Disease Biology, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.1542\/peds.2006-1212","article-title":"Prevalence of Fatty Liver in Children and Adolescents","volume":"118","author":"Schwimmer","year":"2006","journal-title":"Pediatrics"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Anderson, E.L., Howe, L.D., Jones, H.E., Higgins, J.P.T., Lawlor, D.A., and Fraser, A. 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