TY - JOUR
T1 - A Systems Analysis of Phenotype Heterogeneity in APOE*3Leiden.CETP Mice Induced by Long-Term High-Fat High-Cholesterol Diet Feeding
AU - Paalvast, Yared
AU - Zhou, Enchen
AU - Rozendaal, Yvonne J. W.
AU - Wang, Yanan
AU - Gerding, Albert
AU - van Dijk, Theo H.
AU - de Boer, Jan Freark
AU - Rensen, Patrick C. N.
AU - van Dijk, Ko Willems
AU - Kuivenhoven, Jan A.
AU - Bakker, Barbara M.
AU - van Riel, Natal A. W.
AU - Groen, Albert K.
N1 - Funding Information: This work was funded by grants from the European Union, grant FP7-HEALTH n 305707; acronym RESOLVE (YP, JAK, YJWR, NAWR and AKG) and FP7-603091; Acronym TransCard as well as the Netherlands CardioVascular Research Initiative: “the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development and the Royal Netherlands Academy of Sciences” (CVON2017-2020; Acronym Genius2 to JAK and PCNR). JAK and PCNR are Established Investigators of the Netherlands Heart Foundation (2015T068 and 2009T038). Publisher Copyright: © 2022 by the authors.
PY - 2022/11/1
Y1 - 2022/11/1
N2 - Within the human population, considerable variability exists between individuals in their susceptibility to develop obesity and dyslipidemia. In humans, this is thought to be caused by both genetic and environmental variation. APOE*3-Leiden.CETP mice, as part of an inbred mouse model in which mice develop the metabolic syndrome upon being fed a high-fat high-cholesterol diet, show large inter-individual variation in the parameters of the metabolic syndrome, despite a lack of genetic and environmental variation. In the present study, we set out to resolve what mechanisms could underlie this variation. We used measurements of glucose and lipid metabolism from a six-month longitudinal study on the development of the metabolic syndrome. Mice were classified as mice with either high plasma triglyceride (responders) or low plasma triglyceride (non-responders) at the baseline. Subsequently, we fitted the data to a dynamic computational model of whole-body glucose and lipid metabolism (MINGLeD) by making use of a hybrid modelling method called Adaptations in Parameter Trajectories (ADAPT). ADAPT integrates longitudinal data, and predicts how the parameters of the model must change through time in order to comply with the data and model constraints. To explain the phenotypic variation in plasma triglycerides, the ADAPT analysis suggested a decreased cholesterol absorption, higher energy expenditure and increased fecal fatty acid excretion in non-responders. While decreased cholesterol absorption and higher energy expenditure could not be confirmed, the experimental validation demonstrated that the non-responders were indeed characterized by increased fecal fatty acid excretion. Furthermore, the amount of fatty acids excreted strongly correlated with bile acid excretion, in particular deoxycholate. Since bile acids play an important role in the solubilization of lipids in the intestine, these results suggest that variation in bile acid homeostasis may in part drive the phenotypic variation in the APOE*3-Leiden.CETP mice.
AB - Within the human population, considerable variability exists between individuals in their susceptibility to develop obesity and dyslipidemia. In humans, this is thought to be caused by both genetic and environmental variation. APOE*3-Leiden.CETP mice, as part of an inbred mouse model in which mice develop the metabolic syndrome upon being fed a high-fat high-cholesterol diet, show large inter-individual variation in the parameters of the metabolic syndrome, despite a lack of genetic and environmental variation. In the present study, we set out to resolve what mechanisms could underlie this variation. We used measurements of glucose and lipid metabolism from a six-month longitudinal study on the development of the metabolic syndrome. Mice were classified as mice with either high plasma triglyceride (responders) or low plasma triglyceride (non-responders) at the baseline. Subsequently, we fitted the data to a dynamic computational model of whole-body glucose and lipid metabolism (MINGLeD) by making use of a hybrid modelling method called Adaptations in Parameter Trajectories (ADAPT). ADAPT integrates longitudinal data, and predicts how the parameters of the model must change through time in order to comply with the data and model constraints. To explain the phenotypic variation in plasma triglycerides, the ADAPT analysis suggested a decreased cholesterol absorption, higher energy expenditure and increased fecal fatty acid excretion in non-responders. While decreased cholesterol absorption and higher energy expenditure could not be confirmed, the experimental validation demonstrated that the non-responders were indeed characterized by increased fecal fatty acid excretion. Furthermore, the amount of fatty acids excreted strongly correlated with bile acid excretion, in particular deoxycholate. Since bile acids play an important role in the solubilization of lipids in the intestine, these results suggest that variation in bile acid homeostasis may in part drive the phenotypic variation in the APOE*3-Leiden.CETP mice.
KW - APOE3
KW - CETP
KW - bile acid
KW - cholesterol
KW - computational modeling
KW - energy expenditure
KW - metabolic syndrome
KW - triglycerides
UR - http://www.scopus.com/inward/record.url?scp=85142647647&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/nu14224936
DO - https://doi.org/10.3390/nu14224936
M3 - Article
C2 - 36432620
SN - 2072-6643
VL - 14
JO - NUTRIENTS
JF - NUTRIENTS
IS - 22
M1 - 4936
ER -