A new combined multicompartmental model for apolipoprotein B-100 and triglyceride metabolism in VLDL subfractions

Adiels, Martin; Packard, Chris J.; Caslake, Muriel; Stewart, Philip; Soro, Aino; Westerbacka, Jukka; Wennberg, Bernt; Olofsson, Sven-Olof; Taskinen, Marja‐Riitta; Borén, Jan

doi:10.1194/jlr.m400108-jlr200

Cited by 111 publications

(156 citation statements)

References 30 publications

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“…Stable isotope tracers have been used in conjunction with compartmental modelling to elucidate the kinetics of apoB (a key structural protein in lipoproteins) and triglyceride across VLDL subfractions simultaneously. Adiels' model [2] has proven to be a particularly useful tool in determining how physiological features impact VLDL size and dyslipidemia [4,3,39,38]. A more in-depth model of VLDL assembly has been proposed by Shorten and Upreti [50] in which the lipid composition of secreted VLDLs can be determined from uptake of individual free fatty acids after elongation and desaturation by liver enzymes.…”

Section: Introductionmentioning

confidence: 99%

Mathematical modelling of hepatic lipid metabolism

Pratt

Wattis

Salter

2015

Mathematical Biosciences

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The aim of this paper is to develop a mathematical model capable of simulating the metabolic response to a variety of mixed meals in fed and fasted conditions with particular emphasis placed on the hepatic triglyceride element of the model. Model validation is carried out using experimental data for the ingestion of three mixed composition meals over a 24-hour period. Comparison with experimental data suggests the model predicts key plasma lipids accurately given a prescribed insulin profile. One counter-intuitive observation to arise from simulations is that liver triglyceride initially decreases when a high fat meal is ingested, a phenomenon potentially explained by the carbohydrate portion of the meal raising plasma insulin.

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Section: Introductionmentioning

confidence: 99%

Mathematical modelling of hepatic lipid metabolism

Pratt

Wattis

Salter

2015

Mathematical Biosciences

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“…Serum steroids (cortisol, dehydroepiandrosterone, and androstenedione) were measured by liquid chromatography/tandem mass spectrometry using a Waters Xevo mass spectrometer with Acquity uPLC system as described previously 22. [ 2 H 5 ]glycerol in plasma, VLDL 1 and VLDL 2 ‐TG (to trace TG) and [ 2 H 3 ]leucine in plasma, and VLDL 1 ‐and VLDL 2 ‐apoB (to trace whole particles) were measured by gas chromatography–mass spectrometry 23. [U‐ 13 C]palmitic acid was measured in plasma NEFA and VLDL 1 and VLDL 2 ‐TG by gas chromatography–mass spectrometry20 and the proportion of fatty acids (Fas) in VLDL‐TG that were derived from nonsystemic sources was calculated,20 assuming that 16:0 is representative of all FAs.…”

Section: Methodsmentioning

confidence: 99%

Menopausal Status and Abdominal Obesity Are Significant Determinants of Hepatic Lipid Metabolism in Women

Hodson

Banerjee

Rial

et al. 2015

JAHA

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BackgroundAndroid fat distribution (abdominal obesity) is associated with insulin resistance, hepatic steatosis, and greater secretion of large very low‐density lipoprotein (VLDL) particles in men. Since abdominal obesity is becoming increasingly prevalent in women, we aimed to investigate the relationship between android fat and hepatic lipid metabolism in pre‐ and postmenopausal women.Methods and ResultsWe used a combination of stable isotope tracer techniques to investigate intrahepatic fatty acid synthesis and partitioning in 29 lean and 29 abdominally obese women (android fat/total fat 0.065 [0.02 to 0.08] and 0.095 [0.08 to 0.11], respectively). Thirty women were premenopausal aged 35 to 45 and they were matched for abdominal obesity with 28 postmenopausal women aged 55 to 65. As anticipated, abdominal obese women were more insulin resistant with enhanced hepatic secretion of large (404±30 versus 268±26 mg/kg lean mass, P<0.001) but not small VLDL (160±11 versus 142±13). However, postmenopausal status had a pronounced effect on the characteristics of small VLDL particles, which were considerably triglyceride‐enriched (production ratio of VLDL 2‐ triglyceride:apolipoprotein B 30±5.3 versus 19±1.6, P<0.05). In contrast to postmenopausal women, there was a tight control of hepatic fatty acid metabolism and triglyceride production in premenopausal women, whereby oxidation (r s=−0.49, P=0.006), de novo lipogenesis (r s=0.55, P=0.003), and desaturation (r s=0.48, P=0.012) were closely correlated with abdominal obesity‐driven large VLDL‐triglyceride secretion rate.ConclusionsIn women, abdominal obesity is a major driver of hepatic large VLDL particle secretion, whereas postmenopausal status was characterized by increased small VLDL particle size. These data provide a mechanistic basis for the hyperlipidemia observed in postmenopausal obesity.

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“…Signaling-Overproduction of VLDL TG occurs in diabetes and metabolic syndrome and is associated with an increase in VLDL particle size (25,26). To determine whether increased hepatic TG secretion in HSKO mice is associated with secretion of larger, more buoyant VLDL, pooled plasma (n ϭ 3) was fractionated by density gradient ultracentrifugation into VLDL1 (S f ϭ 100 -400) and VLDL2 (S f ϭ 20 -100).…”

Section: Loss Of Hepatocyte Abca1 Expression Increases Nascent Vldl Smentioning

confidence: 99%

Targeted Deletion of Hepatocyte ABCA1 Leads to Very Low Density Lipoprotein Triglyceride Overproduction and Low Density Lipoprotein Hypercatabolism

Chung

Timmins

Duong

et al. 2010

Journal of Biological Chemistry

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Loss of ABCA1 activity in Tangier disease (TD) is associated with abnormal apoB lipoprotein (Lp) metabolism in addition to the complete absence of high density lipoprotein (HDL). We used hepatocyte-specific ABCA1 knock-out (HSKO) mice to test the hypothesis that hepatic ABCA1 plays dual roles in regulating Lp metabolism and nascent HDL formation. HSKO mice recapitulated the TD lipid phenotype with postprandial hypertriglyceridemia, markedly decreased LDL, and near absence of HDL. Triglyceride (TG) secretion was 2-fold higher in HSKO compared with wild type mice, primarily due to secretion of larger TG-enriched VLDL secondary to reduced hepatic phosphatidylinositol 3-kinase signaling. HSKO mice also displayed delayed clearance of postprandial TG and reduced post-heparin plasma lipolytic activity. In addition, hepatic LDLr expression and plasma LDL catabolism were increased 2-fold in HSKO compared with wild type mice. Last, adenoviral repletion of hepatic ABCA1 in HSKO mice normalized plasma VLDL TG and hepatic phosphatidylinositol 3-kinase signaling, with a partial recovery of HDL cholesterol levels, providing evidence that hepatic ABCA1 is involved in the reciprocal regulation of apoB Lp production and HDL formation. These findings suggest that altered apoB Lp metabolism in TD subjects may result from hepatic VLDL TG overproduction and increased hepatic LDLr expression and highlight hepatic ABCA1 as an important regulatory factor for apoB-containing Lp metabolism. ABCA1 (ATP-binding cassette transporter A1) is indispensable in the initial steps of high density lipoprotein (HDL)2 formation and the process of reverse cholesterol transport from peripheral tissues to the liver. ABCA1 is expressed in many cells; however, hepatocytes make the single most important contribution to plasma HDL concentration (1-3). Mutations in ABCA1 in humans cause Tangier disease (TD), an autosomal recessive disorder characterized by severe HDL deficiency, rapid plasma clearance of HDL and apoA-I, sterol deposition in tissues, and premature coronary atherosclerosis (4 -7). In addition to HDL deficiency, TD subjects have significantly elevated plasma TG and a 50% reduction in LDL cholesterol concentrations (4,8). The TG phenotype in TD disease is complicated, with most, but not all, TD subjects displaying elevated fasting or postprandial TG elevations (9). Clee et al. (8) reported an inverse relationship between dysfunctional ABCA1 alleles and plasma TG concentrations. In addition, data from case reports of 59 Tangier patients show variable TG concentrations, with mean, median, minimum, and maximum concentrations of 210, 175, 40, and 580 mg/dl, respectively (4). The underlying mechanisms for the increased plasma TG and decreased LDL concentrations in TD subjects have not been established. In one study, apoA-II enrichment of VLDL of TD subjects was proposed to result in reduced reactivity of VLDL with lipoprotein lipase (LPL) (9, 10). Another study suggested that ABCA1-dependent cholesterol efflux decreases VLDL secretion from murine hep...

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A new combined multicompartmental model for apolipoprotein B-100 and triglyceride metabolism in VLDL subfractions

Cited by 111 publications

References 30 publications

Mathematical modelling of hepatic lipid metabolism

Mathematical modelling of hepatic lipid metabolism

Menopausal Status and Abdominal Obesity Are Significant Determinants of Hepatic Lipid Metabolism in Women

Targeted Deletion of Hepatocyte ABCA1 Leads to Very Low Density Lipoprotein Triglyceride Overproduction and Low Density Lipoprotein Hypercatabolism

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