Lipoprotein Metabolism in Obesity and Diabetes: Insights from Stable Isotope Kinetic Studies in Humans

The metabolic syndrome encapsulates visceral obesity, insulin resistance, diabetes, hypertension and dyslipidaemia. Dyslipidaemia is a cardinal feature of the metabolic syndrome that accelerates the risk of cardiovascular disease. It is usually characterized by high plasma concentrations of triacylglycerol (triglyceride)-rich and apoB (apolipoprotein B)-containing lipoproteins, with depressed concentrations of HDL (high-density lipoprotein). However, lipoprotein metabolism is complex and abnormal plasma concentrations can result from alterations in the rates of production and/or catabolism of these lipoprotein particles. Our in vivo understanding of kinetic defects in lipoprotein metabolism in the metabolic syndrome has been achieved chiefly by ongoing developments in the use of stable isotope tracers and mathematical modelling. This review deals with the methodological aspects of stable isotope kinetic studies. The design of in vivo turnover studies requires considerations related to stable isotope tracer administration, duration of sampling protocol and interpretation of tracer data, all of which are critically dependent on the kinetic properties of the lipoproteins under investigation. Such models provide novel insight that further understanding of metabolic disorders and effects of treatments. Future investigations of the pathophysiology and therapy of the dyslipoproteinaemia of the metabolic syndrome will require the development of novel kinetic methodologies. Specifically, new stable isotope techniques are required for investigating in vivo the turnover of the HDL subpopulation of particles, as well as the cellular efflux of cholesterol into the extracellular space and its subsequent transport in plasma and metabolic fate in the liver.

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Oxazolinone derivative of leucine for GC-MS: a sensitive and robust method for stable isotope kinetic studies of lipoproteins

The Journal of Lipid Research ◽

10.1016/s0022-2275(20)30177-2 ◽

2002 ◽

Vol 43 (2) ◽

pp. 344-349 ◽

Cited By ~ 7

Author(s):

Kevin P. Dwyer ◽

P. Hugh R. Barrett ◽

Dick Chan ◽

Jock I. Foo ◽

Gerald F. Watts ◽

...

Keyword(s):

Stable Isotope ◽

Kinetic Studies ◽

Robust Method

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In vivo kinetic studies to further understand pathogenesis of abnormal lipoprotein metabolism in chronic kidney disease

Clinical and Experimental Nephrology ◽

10.1007/s10157-013-0881-x ◽

2013 ◽

Vol 18 (2) ◽

pp. 261-264 ◽

Cited By ~ 5

Author(s):

Katsunori Ikewaki

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Lipoprotein Metabolism ◽

Kinetic Studies

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Abstract 675: Contrasting Effects of Dietary Carbohydrate Compared to Mono-unsaturated Fat on Hepatic Production of ApoE and ApoC-III Containing VLDL, and Formation of LDL

Circulation ◽

10.1161/circ.116.suppl_16.ii_125-b ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Chunyu Zheng ◽

Christina Khoo ◽

Frank M Sacks

Keyword(s):

Dietary Intervention ◽

Isotope Labeling ◽

Lipoprotein Metabolism ◽

Kinetic Studies ◽

High Plasma ◽

Dietary Carbohydrate ◽

Unsaturated Fat ◽

Downstream Effects ◽

Mufa Diet ◽

Secretion Rates

The effects of substituting dietary carbohydrate (CHO) with mono-unsaturated fat (MUFA) on plasma apoB metabolism were evaluated in 12 adults: 6 with normal and 6 with high plasma triglyceride levels. They consumed for 3 weeks each time a high CHO diet (48% complex CHO, 8% MUFA) and a high MUFA diet (31% complex CHO, 24% MUFA). ApoB100 kinetic studies were performed at the end of each dietary intervention using stable isotope labeling with a bolus and a primed continuous infusion. Multiple VLDL, IDL, and LDL fractions were prepared according to their apoE and apoC-III content. Compared to the CHO diet, the MUFA diet increased the percentage of VLDL and IDL secreted with both apoE and apoC-III (45% on MUFA vs. 14% on CHO, p < 0.01) and reduced the percentage of VLDL and IDL secreted without either apoE or apoC-III (MUFA 19% vs. CHO 40%, p = 0.02). Total liver secretion rates of apoB100 lipoproteins were similar between diets (MUFA 11.6 vs. CHO 11.3 mg·day −1 ·kg −1 , p = NS). The dietary change did not affect the fractional catabolic rates and flux patterns of the lipoproteins. On both diets, VLDL and IDL that had apoE were rapidly cleared from the circulation, limiting LDL formation; whereas lipoproteins that did not have apoE or apoCIII mostly underwent lipolysis with little direct clearance, and were the main precursors of LDL. As a result, increased secretion of VLDL and IDL containing apoE and apoC-III caused by the MUFA diet was associated with higher direct clearance and lower LDL production rates (p = 0.02 vs. CHO), while the CHO diet increased LDL production due to increased secretion of VLDL without apoE or apoC-III. In conclusion, our results reveal a strong dietary effect on the secretion pattern of apoB100 lipoproteins. Substituting dietary complex carbohydrate with mono-unsaturated fat selectively promotes liver secretion of VLDL and IDL containing both apoE and apoC-III while suppressing the secretion of VLDL and IDL without apoE or apoC-III. This leads to significant downstream effects on LDL formation due to differential effects of apoE and apoC-III on apoB lipoprotein metabolism, resulting in enhanced particle clearance and reduced LDL formation with the MUFA diet compared to the CHO diet.

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Ion Trap Mass Spectrometry for Kinetic Studies of Stable Isotope Labeled Vitamin A at Low Enrichments

Analytical Chemistry ◽

10.1021/ac970816r ◽

1998 ◽

Vol 70 (7) ◽

pp. 1369-1374 ◽

Cited By ~ 8

Author(s):

Stephen R. Dueker ◽

Roger S. Mercer ◽

A. Daniel Jones ◽

Andrew J. Clifford

Keyword(s):

Mass Spectrometry ◽

Stable Isotope ◽

Vitamin A ◽

Ion Trap ◽

Kinetic Studies ◽

Ion Trap Mass Spectrometry

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Cholesteryl ester transfer protein (CETP) increases postprandial triglyceridaemia and delays triacylglycerol plasma clearance in transgenic mice

Biochemical Journal ◽

10.1042/bj20081299 ◽

2009 ◽

Vol 419 (3) ◽

pp. 629-634 ◽

Cited By ~ 13

Author(s):

Alessandro G. Salerno ◽

Patrícia R. Patrício ◽

Jairo A. Berti ◽

Helena C. F. Oliveira

Keyword(s):

Cholesteryl Ester ◽

Cholesteryl Ester Transfer Protein ◽

Plasma Clearance ◽

Low Density Lipoprotein ◽

Lipoprotein Metabolism ◽

Density Lipoprotein ◽

Kinetic Studies ◽

Cholesteryl Oleate ◽

Liver Uptake ◽

Transfer Protein

The CETP (cholesteryl ester transfer protein) is a plasma protein synthesized in several tissues, mainly in the liver; CETP reduces plasma HDL (high-density lipoprotein) cholesterol and increases the risk of atherosclerosis. The effect of CETP levels on postprandial intravascular metabolism of TAGs (triacylglycerols) is an often-overlooked aspect of the relationship between CETP and lipoprotein metabolism. Here, we tested the hypothesis that CETP delays the plasma clearance of TAG-rich lipoprotein by comparing human CETP expressing Tg (transgenic) and non-Tg mice. After an oral fat load, the postprandial triglyceridaemia curve was markedly increased in CETP-Tg compared with non-Tg mice (280±30 versus 190±20 mg/dl per 6 h respectively, P<0.02). No differences in intestinal fat absorption and VLDL (very-low-density lipoprotein) secretion rates were observed. Kinetic studies of double-labelled chylomicron-like EMs (emulsions) showed that both [3H]triolein and [14C]cholesteryl oleate FCRs (fractional clearance rates) were significantly reduced (∼20%) in CETP-Tg mice. Furthermore, TAG from lipid EM pre-incubated with CETP-Tg plasma had plasma clearance and liver uptake significantly lower than the non-Tg plasma-treated lipid EM. In addition, reductions in post-heparin plasma LPL (lipoprotein lipase) activity (50%) and adipose tissue mRNA abundance (39%) were verified in CETP-Tg mice. Therefore we conclude that CETP expression in Tg mice delays plasma clearance and liver uptake of TAG-rich lipoproteins by two mechanisms: (i) transferring TAG to HDLs and increasing CE content of the remnant particles and (ii) by diminishing LPL expression. These findings show that the level of CETP expression can influence the responsiveness to dietary fat and may lead to fat intolerance.

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New Insights Into the Regulation of Lipoprotein Metabolism by PCSK9: Lessons From Stable Isotope Tracer Studies in Human Subjects

Frontiers in Physiology ◽

10.3389/fphys.2021.603910 ◽

2021 ◽

Vol 12 ◽

Author(s):

Qidi Ying ◽

Dick C. Chan ◽

Gerald F. Watts

Keyword(s):

Ldl Cholesterol ◽

Plasma Lipids ◽

Human Subjects ◽

High Risk Patient ◽

Lipoprotein Metabolism ◽

Kinetic Studies ◽

Atherosclerotic Cardiovascular Disease ◽

Healthy Individuals ◽

Ldl Particles ◽

Pcsk9 Inhibition

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a convertase enzyme mostly produced by the liver. It is a key regulator of LDL metabolism because of its ability to enhance degradation of the LDL receptor. PCSK9 also regulates the metabolism of lipoprotein(a) [Lp(a)] and triglyceride-rich lipoproteins (TRLs). Its key role in modulating atherosclerotic cardiovascular disease (ASCVD) is supported by genetic studies and clinical outcome trials. Kinetic studies provide mechanistic insight into the role of PCSK9 in regulating the physiology and pathophysiology of plasma lipids and lipoproteins. Kinetic data have demonstrated that plasma PCSK9 concentration is inversely associated with the clearance of LDL in men. Gain-of-function mutations of PCSK9 markedly increase plasma LDL-cholesterol concentrations due to impaired LDL-apoB catabolism. Conversely, PCSK9 deficiency results in low LDL-cholesterol associated with enhanced LDL-apoB clearance. Inhibition of PCSK9 with monoclonal antibodies (such as evolocumab or alirocumab) lowers plasma LDL-cholesterol and apoB levels chiefly by upregulating the catabolism of LDL particles in healthy individuals. As monotherapy, PCSK9 inhibitor reduced Lp(a) concentrations by decreasing the production rate. However, as combination therapy, it reduced the plasma concentration of Lp(a) by increasing the fractional catabolism of Lp(a) particles. In statin-treated patients with high Lp(a), PCSK9 inhibition lowers plasma Lp(a) concentrations by accelerating the catabolism of Lp(a) particles. The effect of PCSK9 inhibition on TRL metabolism has been studied in healthy individuals and in patients with type 2 diabetes. These findings suggest that PCSK9 appears to play a less important role in TRL than LDL metabolism. Kinetic studies of PCSK9 inhibition therapy on lipoprotein metabolism in diverse high risk patient populations (such as familial hypercholesterolemia) and new therapeutic combination also merit further investigation.

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Carbamazepine increases atherogenic lipoproteins: mechanism of action in male adults

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00580.2001 ◽

2002 ◽

Vol 282 (2) ◽

pp. H704-H716 ◽

Cited By ~ 19

Author(s):

Susanne Brämswig ◽

Anja Kerksiek ◽

Thomas Sudhop ◽

Claus Luers ◽

Klaus Von Bergmann ◽

...

Keyword(s):

Isotope Labeling ◽

Low Density Lipoprotein ◽

Lipoprotein Metabolism ◽

Density Lipoprotein ◽

Mevalonic Acid ◽

Kinetic Studies ◽

Low Density ◽

Production Rates ◽

Underlying Mechanisms ◽

Cholesterol Precursors

Treatment with carbamazepine (CBZ) affects cholesterol concentrations, but little is known about the precise nature and underlying mechanisms of changes in lipoprotein metabolism. We investigated prospectively the effects of CBZ on lipid metabolism in normolipemic adults. In 21 healthy males, lipoprotein and noncholesterol sterol concentrations were measured before and during treatment with CBZ for 70 ± 18 days. Thirteen subjects underwent kinetic studies of apolipoprotein-B (ApoB) metabolism with the use of endogenous stable isotope labeling. Lipoprotein kinetic parameters were calculated by multicompartmental modeling. Significant increases in total cholesterol, in ApoB-containing lipoproteins [very-low-density lipoprotein (VLDL), intermediate density lipoprotein (IDL), and low-density lipoprotein (LDL)], and in triglycerides, but not in high-density lipoprotein (HDL), were observed. Lipoprotein particle composition remained unchanged. Mean fractional catabolic and production rates of ApoB-containing lipoproteins were not significantly different, although mean production rates of VLDL and IDL were substantially increased (+46 ± 139% and +30 ± 97%, respectively), whereas mean production of LDL remained unchanged (+2.1 ± 45.6%). Cholestanol in serum increased significantly but not the concentrations of plant sterols (campesterol, sitosterol) and the cholesterol precursors (lathosterol, mevalonic acid). There was a significant correlation between the decrease in free thyroxine and the increase in IDL cholesterol. Treatment with CBZ increases mainly ApoB-containing lipoproteins. CBZ seems not to influence endogenous cholesterol synthesis or intestinal absorption directly. The increase is neither related to increased ApoB production nor to decreased catabolism but is rather due to changes in the conversion cascade of IDL particles, most likely as an indirect effect through a decrease in thyroid hormones.

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