first_pagesettingsOrder Article ReprintsOpen AccessArticleDietary Long-Chain Fatty Acids Accelerate Metabolic Dysfunction in Guinea Pigs with Non-Alcoholic Steatohepatitisby Kamilla Pedersen 1ORCID,David Højland Ipsen 1,2,Josephine Skat-Rørdam 1ORCID,Jens Lykkesfeldt 1ORCID andPernille Tveden-Nyborg 1,*ORCID1Section of Experimental Animal Models, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg, Denmark2Integrated Physiology Research, Obesity and NASH Pharmacology, Novo Nordisk A/S, 2760 Måløv, Denmark*Author to whom correspondence should be addressed.Nutrients 2023, 15(11), 2445; https://doi.org/10.3390/nu15112445Received: 18 April 2023 / Revised: 17 May 2023 / Accepted: 22 May 2023 / Published: 24 May 2023(This article belongs to the Section Lipids)Download Browse Figures Versions NotesAbstractThe composition of dietary fatty acids may be important for the development and progression of metabolic syndrome and non-alcoholic steatohepatitis (NASH). This study investigated the effect of two high-fat diets based on coconut oil, containing predominantly medium-chain fatty acids (MCFA), or cocoa butter, containing mainly long-chain fatty acids (LCFA), on glucose homeostasis and NASH in guinea pigs following 16 and 32 weeks of diet. At week 16, glucose intolerance was increased in the LCFA animals compared to the MCFA animals (p < 0.001), with both groups differing from the controls by week 32 (p < 0.0001), supported by increased hemoglobin A1c (p < 0.05). NASH was present in both high-fat groups from week 16, with advancing fibrosis appearing more progressive in the LCFA animals at week 16. In agreement, gene expression showed overall increased expression of NASH target genes in the LCFA animals compared to the MCFA animals at weeks 16 and 32 (p < 0.05 and p < 0.0001, respectively). The LCFA animals also displayed increased plasma uric acid at both time points (p < 0.05), a phenomenon linked to NASH in humans. In conclusion, this study reports that a diet high in LCFA promotes metabolic imbalance and may accelerate NASH-associated hepatic fibrosis. This highlights the importance of a critical evaluation of fatty acid composition when investigating NASH-associated endpoints.