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Agent-Based Modeling Predicts HDL-Independent Pathway of Removal of Excess Surface

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Agent-Based Modeling Predicts HDL-Independent Pathway of Removal of Excess Surface bioRxiv preprint doi: https://doi.org/10.1101/398164; this version posted August 22, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 Agent-Based Modeling Predicts HDL-independent Pathway of Removal of Excess Surface 2 Lipids from Very Low Density Lipoprotein 3 4 Yared Paalvast1*, Jan Albert Kuivenhoven1, Barbara M. Bakker1, Albert .K. Groen2,3 5 6 1. Laboratory of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 AV 7 Groningen, The Netherlands 8 2. Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, 9713 9 AV Groningen, The Netherlands 10 3. Laboratory of Experimental Vascular Medicine, University of Amsterdam, Amsterdam UMC, location 11 Meibergdreef, 1105 AZ Amsterdam, The Netherlands 12 13 14 *To whom correspondence should be addressed: 15 E-Mail: [email protected] 16 17 Running title: Agent-Based Modeling Predicts HDL-independent Pathway 18 19 20 21 Abbreviations: 22 PR (production rate), FCR (fractional catabolic rate), ppd (pool per day), SRB1 (scavenger receptor 23 B1), EL (endothelial lipase), HL, (hepatic lipase), PLTP (phospholipid transfer protein), CETP 24 (cholesteryl ester transfer protein), FC (free cholesterol), CE (cholesterol ester), PL (phospholipid), 25 LpX (lipoprotein X). 26 27 28 1 bioRxiv preprint doi: https://doi.org/10.1101/398164; this version posted August 22, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 29 Abstract 30 A hallmark of the metabolic syndrome is low HDL-cholesterol coupled with high plasma triglycerides 31 (TG), but it is unclear what drives this close association. Plasma triglycerides and HDL cholesterol are 32 thought to communicate through two distinct mechanisms. Firstly, excess surface lipids from VLDL 33 released during lipolysis are transferred to HDL, thereby contributing to HDL directly but also 34 indirectly through providing substrate for LCAT. Secondly, high plasma TG increases clearance of 35 HDL through core-lipid exchange between VLDL and HDL via CETP and subsequent hydrolysis of 36 the TG in HDL, resulting in smaller HDL and thus increased clearance rates. 37 To test our understanding of how high plasma TG induces low HDL-cholesterol, making use of 38 established knowledge, we developed a comprehensive agent-based model of lipoprotein metabolism 39 which was validated using monogenic disorders of lipoprotein metabolism. 40 By perturbing plasma TG in the model, we tested whether the current theoretical framework 41 reproduces experimental findings. Interestingly, while increasing plasma TG through simulating 42 decreased lipolysis of VLDL resulted in the expected decrease in HDL cholesterol, perturbing plasma 43 TG through simulating increased VLDL production rates did not result in the expected HDL-TG 44 relation at physiological lipid fluxes. However, model perturbations and experimental findings can be 45 reconciled if we assume a pathway removing excess surface-lipid from VLDL that does not contribute 46 to HDL cholesterol ester production through LCAT. In conclusion, our model simulations suggest that 47 excess surface lipid from VLDL is cleared in part independently from HDL. 48 Author summary 49 While it has long been known that high plasma triglycerides are associated with low HDL cholesterol, 50 the reason for this association has remained unclear. One of the proposed mechanisms is that during 51 catabolism of VLDL, lipoproteins rich in triglyceride, the excess surface of these particles become a 52 source for the production of HDL cholesterol, and that therefore decreased catabolism of VLDL will 53 lead to both higher plasma triglyceride and low HDL cholesterol. Another proposed mechanism is that 54 during increased production of VLDL, there will be increased exchange of core lipids between VLDL 2 bioRxiv preprint doi: https://doi.org/10.1101/398164; this version posted August 22, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 55 and HDL, with subsequent hydrolysis of the triglyceride in HDL, leading to smaller HDL that is 56 cleared more rapidly. To investigate these mechanisms further we developed a computational model 57 based on established knowledge concerning lipoprotein metabolism and validated the model with 58 known findings in monogenetic disorders. Upon perturbing the plasma triglycerides within the model 59 by increasing the VLDL production rate, we unexpectedly found an increase in both triglyceride and 60 HDL cholesterol. However, upon assuming that less excess surface lipid is available to HDL, HDL 61 decreases in response to increased VLDL production. We therefore propose that there must be a 62 pathway removing excess surface lipids that is independent from HDL. 63 64 Introduction 65 High plasma triglycerides (TG) and low HDL-cholesterol (HDL-C) are important risk factors for 66 cardiovascular disease [1,2]. Which of these two strongly negatively correlated parameters confers 67 cardiovascular disease risk is still a matter of controversy [3]. It has been suggested that lipolytic 68 activity mediates the correlation between HDL-C and plasma TG [4]. According to this hypothesis 69 triacylglycerol lipolytic activity increases HDL-C as it allows apolipoproteins, phospholipids (PL) and 70 free cholesterol (FC) to be transferred to the HDL-pool [5]. An alternative explanation holds that in 71 conditions with high plasma TG, cholesterol ester transfer protein (CETP) – mediated exchange of 72 HDL – cholesterol ester (CE) with TG from TG-rich lipoproteins is enhanced, thereby decreasing 73 HDL-C [6]. Which of these mechanisms is more important and under what conditions is unclear. The 74 HDL-C and TG plasma concentrations measured are the end result of a multitude of interacting 75 processes. A short introduction to metabolism of apoA-I and apoB-containing lipoproteins is given 76 below. 77 78 HDL metabolism 79 The production of HDL not only depends on the production of its major protein, apolipoprotein (apo) 80 A-I, but also on the activity of ATP binding cassette subfamily A member 1 (ABCA1), and lecithin- 81 cholesterol acyltransferase (LCAT) [7]. Maturation of lipid-poor apoA-I to larger HDL is dependent 3 bioRxiv preprint doi: https://doi.org/10.1101/398164; this version posted August 22, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 82 on LCAT activity on the particle’s surface, resulting in the change of a discoidal 2 or 3 apoA-I 83 molecules harboring disc with PL and FC, to a more spherical particle containing CE in its core [8]. 84 These matured spherical HDL-particles are subject to fusion, a process catalyzed by phospholipid 85 transfer protein (PLTP). This results in both larger particles containing typically 3 to 5 apoA-I 86 molecules as well as shedding of superfluous apoA-I as lipid-poor apoA-I [9]. ApoA-I shedded in this 87 way can then be either recycled for formation of new spherical HDL, or be cleared by the kidneys 88 [10]. Furthermore, HDL interacts with apoB-lipoproteins through CETP-mediated exchange of TG by 89 CE [11]. TG in the core of HDL can then be hydrolyzed by both hepatic (HL) and endothelial lipase 90 (EL) [12,13]. Depletion of the HDL-core will lead to further shedding of lipid-poor apoA-I, which, as 91 stated already, can then either be cleared by the kidneys or be remodeled back into mature HDL [14]. 92 The specific uptake of HDL-CE by the liver through scavenger receptor class B member 1 (SRB1) 93 followed by excretion into the bile is considered to be an important mechanism for cholesterol export 94 from the body. The existence of all these pathways has been demonstrated almost exclusively in in 95 vitro systems. Whether they are important under in vivo conditions has seldom been shown and 96 whether lipoprotein fluxes are in balance when these pathways exclusively describe lipoprotein 97 metabolism has never been shown. 98 99 Metabolism of triglyceride-rich lipoproteins 100 TG-rich lipoproteins, which may be either very-low density lipoprotein (VLDL) produced by the liver 101 or chylomicrons produced by the small intestine, have their triglycerides hydrolyzed by lipoprotein 102 lipase (LPL) in peripheral tissues, becoming progressively smaller as this process continues. For 103 VLDL, HL is considered to facilitate the removal of the remaining portion of TG at the end of this 104 lipolytic cascade [15]. The resulting LDL is mainly taken up in the liver through the action of LDL- 105 receptor (LDLR), thus the same tissue in which apo-B containing lipoproteins are originally produced. 106 In addition to LDLR-mediated uptake, there is also some uptake through LDLR-related protein (LRP) 107 and VLDL-receptor (VLDLR), that facilitate uptake of larger apoB-lipoproteins that have not 108 completely gone through the lipolytic cascade[16]. 109 4 bioRxiv preprint doi: https://doi.org/10.1101/398164; this version posted August 22, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 110 Models of lipoprotein metabolism 111 To get a grip on the complexity of lipoprotein metabolism, several mathematical models have been 112 developed.
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