{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T05:02:52Z","timestamp":1790053372090,"version":"4.0.1"},"reference-count":26,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T00:00:00Z","timestamp":1789862400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["R01 HL166549"],"award-info":[{"award-number":["R01 HL166549"]}]},{"name":"National Institutes of Health","award":["R01 DK123186"],"award-info":[{"award-number":["R01 DK123186"]}]},{"name":"National Institutes of Health","award":["R01 HL169297"],"award-info":[{"award-number":["R01 HL169297"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Introduction: Animal models of cardiac dysfunction and heart failure play important roles in preclinical study and drug discovery. Cardiovascular disease and metabolic dysfunction-associated steatohepatitis (MASH) are closely associated metabolic disorders that frequently coexist in individuals with obesity and metabolic syndrome. However, the mechanisms linking diet-induced metabolic stress to cardiac dysfunction and hepatic pathology remain understudied. Method: In this study, six-week-old C57Bl\/6J male mice were fed standard normal chow or a Gubra Amylin NASH (GAN) diet for six months to investigate the concurrent cardiac and hepatic manifestations. Results: Our results indicated that GAN diet-fed mice developed early cardiac dysfunction characterized by reduced ejection fraction (EF) and impaired diastolic function, as indicated by increased E\/A and E\/E\u2032 ratios. These cardiac changes were accompanied by worsening hepatic pathology, including elevated total cholesterol (TC) and liver injury markers such as ALT, AST and ALP. By 6 months, mice developed pronounced fibrotic remodeling and inflammation in both the heart and liver, as confirmed by histopathological and gene expression analyses. Metabolic assessments further demonstrated a decreased respiratory exchange ratio (RER) in GAN diet-fed mice, particularly during the dark cycle, suggesting enhanced lipid utilization and decreased metabolic flexibility. In addition, reduced oxygen consumption, carbon dioxide production, and locomotor activity suggested impaired energy expenditure and reduced physical activity levels. Conclusion: Collectively, our findings demonstrate that chronic GAN diet feeding induces early cardiac dysfunction accompanied by progressive MASH-like hepatic pathology, with inflammation and fibrotic remodeling developing in both the heart and liver. These findings establish GAN diet feeding as a useful model for investigating the concurrent cardiac and hepatic consequences of chronic metabolic stress.<\/jats:p>","DOI":"10.3390\/nu18183084","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T12:50:03Z","timestamp":1789995003000},"page":"3084","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chronic Dietary Stress Is Associated with Early Cardiac Dysfunction and Progressive MASH Accompanied by Systemic Inflammation and Fibrosis"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6465-9339","authenticated-orcid":false,"given":"Saima Shakil","family":"Malik","sequence":"first","affiliation":[{"name":"Department of Medicine, Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6068-6528","authenticated-orcid":false,"given":"Hua","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Mariam","family":"Hamoudi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Xinchun","family":"Pi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"}]},{"given":"Liang","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"105447","DOI":"10.1016\/j.ebiom.2024.105447","article-title":"The evolving landscape of cardiometabolic diseases","volume":"109","author":"Eroglu","year":"2024","journal-title":"eBioMedicine"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2982","DOI":"10.1016\/j.jacc.2020.11.010","article-title":"Global burden of cardiovascular diseases and risk factors, 1990\u20132019: Update from the GBD 2019 study","volume":"76","author":"Roth","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.ijcard.2015.06.136","article-title":"A high-sugar and high-fat diet impairs cardiac systolic and diastolic function in mice","volume":"198","author":"Carbone","year":"2015","journal-title":"Int. J. Cardiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1038\/s41575-025-01168-3","article-title":"Balancing cholesterol metabolism in the liver and gut: Perspectives in health and disease","volume":"23","author":"Yamauchi","year":"2026","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Yanai, H., Adachi, H., Hakoshima, M., Iida, S., and Katsuyama, H. (2023). Metabolic-dysfunction-associated steatotic liver disease\u2014Its pathophysiology, association with atherosclerosis and cardiovascular disease, and treatments. Int. J. Mol. Sci., 24.","DOI":"10.20944\/preprints202309.1062.v1"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"101231","DOI":"10.1016\/j.mam.2023.101231","article-title":"Liver fibrosis in NAFLD\/NASH: From pathophysiology towards diagnostic and therapeutic strategies","volume":"95","author":"Parola","year":"2024","journal-title":"Mol. Asp. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1038\/s43856-025-00951-2","article-title":"Guideline-directed medical strategies for the co-management of heart failure and metabolic dysfnction-associated steatotic liver disease","volume":"5","author":"Gries","year":"2025","journal-title":"Commun. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e168","DOI":"10.1161\/ATV.0000000000000153","article-title":"Nonalcoholic fatty liver disease and cardiovascular risk: A scientific statement from the American Heart Association","volume":"42","author":"Duell","year":"2022","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1097\/HEP.0000000000000735","article-title":"Metabolic dysfunction-associated steatotic liver disease and the heart","volume":"82","author":"Driessen","year":"2025","journal-title":"Hepatology"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Ahmad Najib, M.S., Elias, M.H., Juliana, N., Sheikh Abdul Kadir, S.H., Ibrahim, E., and Abdul Hamid, N. (2025). The Effects of High-Fat Diet on the Molecular Pathways in Cardiac Tissue: A Systematic Review of In Vivo Rodent Studies and Integrated Bioinformatic Analysis. Biomedicines, 13.","DOI":"10.3390\/biomedicines13092071"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2241","DOI":"10.1002\/hep.30333","article-title":"Mouse models of nonalcoholic steatohepatitis: Toward optimization of their relevance to human nonalcoholic steatohepatitis","volume":"69","author":"Farrell","year":"2019","journal-title":"Hepatology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1038\/s41443-021-00440-9","article-title":"High-fat diet induces obesity in adult mice but fails to develop pre-penile and penile vascular dysfunction","volume":"34","author":"Odom","year":"2022","journal-title":"Int. J. Impot. Res."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Calligaris, S.D., Lecanda, M., Solis, F., Ezquer, M., Gutierrez, J., Brandan, E., Leiva, A., Sobrevia, L., and Conget, P. (2013). Mice long-term high-fat diet feeding recapitulates human cardiovascular alterations: An animal model to study the early phases of diabetic cardiomyopathy. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0060931"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2454","DOI":"10.1111\/febs.70362","article-title":"Comparative analysis of metabolic and functional cardiac alterations in diet-and genetically induced mouse models of cardiac dysfunction","volume":"293","author":"Ott","year":"2026","journal-title":"FEBS J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e70720","DOI":"10.14814\/phy2.70720","article-title":"Renalase deficiency suppresses hepatic triglyceride accumulation in the progression to MASLD\/MASH by GAN diet in male mice","volume":"14","author":"Okano","year":"2026","journal-title":"Physiol. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Hansen, H.H., \u00c6gidius, H.M., Or\u00f3, D., Evers, S.S., Heeb\u00f8ll, S., Eriksen, P.L., Thomsen, K.L., Bengtsson, A., Veidal, S.S., and Feigh, M. (2020). Human translatability of the GAN diet-induced obese mouse model of non-alcoholic steatohepatitis. BMC Gastroenterol., 20.","DOI":"10.1186\/s12876-020-01356-2"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1038\/s42255-023-00844-5","article-title":"CRAT links cholesterol metabolism to innate immune responses in the heart","volume":"5","author":"Mao","year":"2023","journal-title":"Nat. Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1932","DOI":"10.1016\/j.cmet.2022.09.019","article-title":"The rheumatoid arthritis drug auranofin lowers leptin levels and exerts antidiabetic effects in obese mice","volume":"34","author":"Cox","year":"2022","journal-title":"Cell Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.yjmcc.2017.10.006","article-title":"Echocardiographic evaluation of diastolic function in mouse models of heart disease","volume":"114","author":"Schnelle","year":"2018","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"23056","DOI":"10.1038\/s41598-023-50328-5","article-title":"Semaglutide reduces tumor burden in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH-HCC with advanced fibrosis","volume":"13","author":"Hansen","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1038\/s41575-025-01162-9","article-title":"Metabolic dysfunction-associated steatotic liver disease and steatohepatitis-associated hepatocarcinoma preclinical models","volume":"23","author":"Leslie","year":"2026","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1159\/000369782","article-title":"Remodeling of glucose metabolism precedes pressure overload-induced left ventricular hypertrophy: Review of a hypothesis","volume":"130","author":"Kundu","year":"2015","journal-title":"Cardiology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1161\/CIRCRESAHA.121.318241","article-title":"Cardiac energy metabolism in heart failure","volume":"128","author":"Lopaschuk","year":"2021","journal-title":"Circ. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1161\/CIRCULATIONAHA.109.882068","article-title":"Genetic deletion of myostatin from the heart prevents skeletal muscle atrophy in heart failure","volume":"121","author":"Heineke","year":"2010","journal-title":"Circulation"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1210\/er.2017-00211","article-title":"Metabolic flexibility as an adaptation to energy resources and requirements in health and disease","volume":"39","author":"Smith","year":"2018","journal-title":"Endocr. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e186420","DOI":"10.1172\/JCI186420","article-title":"MASH: The nexus of metabolism, inflammation, and fibrosis","volume":"135","author":"Steinberg","year":"2025","journal-title":"J. Clin. Investig."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/18\/3084\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T04:22:17Z","timestamp":1790050937000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/18\/3084"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,20]]},"references-count":26,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["nu18183084"],"URL":"https:\/\/doi.org\/10.3390\/nu18183084","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,20]]}}}