Dietary fat composition shapes bile acid metabolism and severity of liver injury in a pig model of pediatric NAFLD

Authors: MANJARÍN, RODRIGO - California Polytechnic State University; DILLARD, KAYLA - California Polytechnic State University; COFFIN, MORGAN - California Polytechnic State University; HERNANDEZ, GABRIELLA - California Polytechnic State University; SMITH, VICTORIA - California Polytechnic State University; NOLAND-LIDELL, TRISTA - California Polytechnic State University; GEHANI, TANVI - California Polytechnic State University; SMART, HAYDEN - California Polytechnic State University; WHEELER, KEVIN - California Polytechnic State University; SPRAYBERRY, KIMBERLY - California Polytechnic State University; EDWARDS, MARK - California Polytechnic State University; FANTER, ROB - California Polytechnic State University; GLANZ, HUNTER - California Polytechnic State University; IMMOOS, CHAD - California Polytechnic State University; SANTIAGO-RODRIGUEZ, TASHA - Diversigen, Inc; BLANK, JASON - California Polytechnic State University; Burrin, Douglas - Doug; PICCOLO, BRIAN - Arkansas Children'S Nutrition Research Center (ACNC); ABO-ISMAIL, MOHAMMED - California Polytechnic State University; LA FRANO, MICHAEL - California Polytechnic State University; MAJ, MAGDALENA - California Polytechnic State University

Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/9/2022
Publication Date: 7/20/2022
Citation: Manjarin, R., Dillard, K., Coffin, M., Hernandez, G.V., Smith, V.A., Noland-Lidell, T., Gehani, T.R., Smart, H.J., Wheeler, K., Sprayberry, K.A., Edwards, M.S., Fanter, R.K., Glanz, H., Immoos, C., Santiago-Rodriguez, T.M., Blank, J.M., Burrin, D.G., Piccolo, B., Abo-Ismail, M., La Frano, M.R., Maj, M. 2022. Dietary fat composition shapes bile acid metabolism and severity of liver injury in a pig model of pediatric NAFLD. American Journal of Physiology - Endocrinology and Metabolism. 323:E187-E206. https://doi.org/10.1152/ajpendo.00052.2022.
DOI: https://doi.org/10.1152/ajpendo.00052.2022

Interpretive Summary: Non-alcoholic fatty liver disease (NAFLD) represents the major cause of pediatric chronic liver pathology in the U.S. The cause of NAFLD in children has been linked to excessive consumption of a nutrient rich diet, but it is not clear how specific nutrients lead to liver disease. Studies in adult mice suggest that consuming plant fats, such as olive oil and coconut oil, rather than saturated animal fats may reduce the risk of NAFLD. In this study, we used our new model of pediatric NAFLD using a strain of Iberian pigs to test whether different types of fat in a high fat-high fructose diet influence the development of the disease in infant pigs. The aim of this study was to test whether three types of fat, olive oil, coconut oil, or lard oil influence the signs of NAFLD after 10 weeks. Unexpectedly, our results in developing juvenile pigs showed that adding either olive or coconut oil to a high fat-high fructose diet increased the severity of liver disease and liver fat accumulation without causing glucose intolerance or obesity.

Technical Abstract: The objective of this study was to investigate the effect of dietary fatty acid (FA) composition on bile acid (BA) metabolism in a pig model of NAFLD, by using a multiomics approach combined with histology and serum biochemistry. Thirty 20-d-old Iberian pigs pair housed in pens were randomly assigned to receive 1 of 3 hypercaloric diets for 10 weeks: 1) lard-enriched (LAR; n=5 pens), 2) olive oil-enriched (OLI, n=5), and 3) coconut oil-enriched (COC; n=5). Animals were euthanized on week 10 after blood sampling, and liver, colon and distal ileum (DI) were collected for histology, metabolomics, and transcriptomics. Data were analyzed by multivariate and univariate statistics. Compared with OLI and LAR, COC increased primary and secondary BAs in liver, plasma and colon. In addition, both COC and OLI reduced circulating fibroblast growth factor 19, increased hepatic necrosis, composite lesion score, and liver enzymes in serum, and upregulated genes involved in hepatocyte proliferation and DNA repair. The severity of liver disease in COC and OLI pigs was associated with increased levels of phosphatidylcholines, medium-chain triacylglycerides, trimethylamine-N-oxide, and long-chain acylcarnitines in the liver, and the expression of profibrotic markers in DI, but not with changes in the composition or size of BA pool. In conclusion, our results indicate a role of dietary FAs in the regulation of BA metabolism and progression of NAFLD. Interventions that aim to modify the composition of dietary FAs, rather than to regulate BA metabolism or signaling, may be more effective in the treatment of NAFLD.