TY - JOUR
T1 - Saturated fat is more metabolically harmful for the human liver than unsaturated fat or simple sugars
AU - Luukkonen, Panu K.
AU - Sädevirta, Sanja
AU - Zhou, You
AU - Kayser, Brandon
AU - Ali, Ashfaq
AU - Ahonen, Linda
AU - Lallukka, Susanna
AU - Pelloux, Véronique
AU - Gaggini, Melania
AU - Jian, Ching
AU - Hakkarainen, Antti
AU - Lundbom, Nina
AU - Gylling, Helena
AU - Salonen, Anne
AU - Oresic, Matej
AU - Hyötyläinen, Tuulia
AU - Orho-Melander, Marju
AU - Rissanen, Aila
AU - Gastaldelli, Amalia
AU - Clément, Karine
AU - Hodson, Leanne
AU - Yki-Järvinen, Hannele
N1 - Funding Information:
Acknowledgments. The authors gratefully acknowledge Anne Salo, Aila Karioja-Kallio, Päivi Ihamuotila, Pentti Pölönen, Leena Kaipiainen, and Raisa Harjula (Helsinki University Hospital) as well as Catriona Charlton (University of Oxford) for skillful technical assistance, A. Margot Umpleby (University of Surrey) for advice on stable isotope methodology, and Siiri Luukkonen (University of Oulu) for graphical assistance. Funding. This study was supported by grants from Suomen Lääketieteen Säätiö (P.K.L.), Yrjö Jahnssonin Säätiö (P.K.L.), Emil Aaltosen Säätiö (P.K.L.), the Diabetes Research Foundation (P.K.L.), Helsingin Yliopisto (P.K.L. and A.S.), the Elucidating Pathways of Steatohepatitis consortium funded by the Horizon 2020 Frame-work Program of the European Union under grant Agreement EPoS 634413 (B.K., T.H., M.O., A.G., K.C., and H.Y.-J.), Ministero dell’Istruzione, dell’Università e della Ricerca and Consiglio Nazionale delle Ricerche (A.G.), PIA-F-Crin Force program (V.P. and K.C.), the British Heart Foundation Intermediate Fellowship in Basic Science (FS/11/18/ 28633) (L.H.), Suomen Akatemia (H.Y.-J.), the Sigrid Juselius Foundation (H.Y.-J.,), Evo (H.Y.-J.), the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (EMIF 115372, H.Y.-J.), and Novo Nordisk Foundation (H.Y.-J.). Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. P.K.L. contributed to conducting the clinical research; acquisition, analysis, and interpretation of data; and drafting and critical revision of the manuscript. S.S. contributed to study diet design, conducting the clinical research, and critical revision of the manuscript. Y.Z. and B.K. contributed to analysis and interpretation of the data and critical revision of the manuscript. A.A., L.A., S.L., V.P., M.G., C.J., A.H., N.L., H.G., M.O., T.H., M.O.-M., A.G., and K.C. contributed to acquisition of data and critical revision of the manuscript. A.S., A.R., and L.H. contributed to acquisition, analysis, and interpretation of data and to critical revision of the manuscript. H.Y.-J. contributed to study concept and design, analysis and interpretation of the data, drafting and critical revision of the manuscript, and study supervision. H.Y.-J. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this study were presented in abstract form at the 52nd Annual Meeting of the European Association for the Study of Diabetes, Munich, Germany, 12–16 September 2016, and at the 77th Scientific Sessions of the American Diabetes Association, San Diego, CA, 9–13 June 2017.
Publisher Copyright:
© 2018 by the American Diabetes Association.
PY - 2018/8/1
Y1 - 2018/8/1
N2 - OBJECTIVE: Nonalcoholic fatty liver disease (i.e., increased intrahepatic triglyceride [IHTG] content), predisposes to type 2 diabetes and cardiovascular disease. Adipose tissue lipolysis and hepatic de novo lipogenesis (DNL) are the main pathways contributing to IHTG. We hypothesized that dietary macronutrient composition influences the pathways, mediators, and magnitude of weight gain-induced changes in IHTG. RESEARCH DESIGN AND METHODS: We overfed 38 overweight subjects (age 48 ± 2 years, BMI 31 ± 1 kg/m2, liver fat 4.7 ± 0.9%) 1,000 extra kcal/day of saturated (SAT) or unsaturated (UNSAT) fat or simple sugars (CARB) for 3 weeks. We measured IHTG (1H-MRS), pathways contributing to IHTG (lipolysis ([2H5]glycerol) and DNL (2H2O) basally and during euglycemic hyperinsulinemia), insulin resistance, endotoxemia, plasma ceramides, and adipose tissue gene expression at 0 and 3 weeks. RESULTS: Overfeeding SAT increased IHTG more (+55%) than UNSAT (+15%, P < 0.05). CARB increased IHTG (+33%) by stimulating DNL (+98%). SAT significantly increased while UNSAT decreased lipolysis. SAT induced insulin resistance and endotoxemia and significantly increased multiple plasma ceramides. The diets had distinct effects on adipose tissue gene expression. CONCLUSIONS: Macronutrient composition of excess energy influences pathways of IHTG: CARB increases DNL, while SAT increases and UNSAT decreases lipolysis. SAT induced the greatest increase in IHTG, insulin resistance, and harmful ceramides. Decreased intakes of SAT could be beneficial in reducing IHTG and the associated risk of diabetes.
AB - OBJECTIVE: Nonalcoholic fatty liver disease (i.e., increased intrahepatic triglyceride [IHTG] content), predisposes to type 2 diabetes and cardiovascular disease. Adipose tissue lipolysis and hepatic de novo lipogenesis (DNL) are the main pathways contributing to IHTG. We hypothesized that dietary macronutrient composition influences the pathways, mediators, and magnitude of weight gain-induced changes in IHTG. RESEARCH DESIGN AND METHODS: We overfed 38 overweight subjects (age 48 ± 2 years, BMI 31 ± 1 kg/m2, liver fat 4.7 ± 0.9%) 1,000 extra kcal/day of saturated (SAT) or unsaturated (UNSAT) fat or simple sugars (CARB) for 3 weeks. We measured IHTG (1H-MRS), pathways contributing to IHTG (lipolysis ([2H5]glycerol) and DNL (2H2O) basally and during euglycemic hyperinsulinemia), insulin resistance, endotoxemia, plasma ceramides, and adipose tissue gene expression at 0 and 3 weeks. RESULTS: Overfeeding SAT increased IHTG more (+55%) than UNSAT (+15%, P < 0.05). CARB increased IHTG (+33%) by stimulating DNL (+98%). SAT significantly increased while UNSAT decreased lipolysis. SAT induced insulin resistance and endotoxemia and significantly increased multiple plasma ceramides. The diets had distinct effects on adipose tissue gene expression. CONCLUSIONS: Macronutrient composition of excess energy influences pathways of IHTG: CARB increases DNL, while SAT increases and UNSAT decreases lipolysis. SAT induced the greatest increase in IHTG, insulin resistance, and harmful ceramides. Decreased intakes of SAT could be beneficial in reducing IHTG and the associated risk of diabetes.
UR - http://www.scopus.com/inward/record.url?scp=85052752226&partnerID=8YFLogxK
U2 - 10.2337/dc18-0071
DO - 10.2337/dc18-0071
M3 - Article
C2 - 29844096
AN - SCOPUS:85052752226
VL - 41
SP - 1732
EP - 1739
JO - Diabetes Care
JF - Diabetes Care
SN - 0149-5992
IS - 8
ER -