Thematic review series: Patient-Oriented Research. What we have learned about VLDL and LDL metabolism from human kinetics studies

Parhofer, Klaus G.; Barrett, P. Hugh R.

doi:10.1194/jlr.r600013-jlr200

Cited by 51 publications

(30 citation statements)

References 106 publications

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“…Several published reports support the concept that depletion of a hepatic pool of cholesterol can decrease VLDL secretion (39)(40)(41)(42)(43). In some cases, reduction of hepatic cholesterol levels decreases only the number and not the cholesterol or TG content of secreted VLDL particles.…”

Section: Discussionmentioning

confidence: 80%

Hepatic ABCG5/G8 overexpression reduces apoB-lipoproteins and atherosclerosis when cholesterol absorption is inhibited

Basso

Freeman

et al. 2007

Journal of Lipid Research

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We previously reported that liver-specific overexpression of ABCG5/G8 in mice is not atheroprotective, suggesting that increased biliary cholesterol secretion must be coupled with decreased intestinal cholesterol absorption to increase net sterol loss from the body and reduce atherosclerosis. To evaluate this hypothesis, we fed low density lipoprotein receptor-knockout (LDLr-KO) control and ABCG5/ G8-transgenic (ABCG5/G8-Tg)3LDLr-KO mice, which overexpress ABCG5/G8 only in liver, a Western diet containing ezetimibe to reduce intestinal cholesterol absorption. On this dietary regimen, liver-specific ABCG5/G8 overexpression increased hepatobiliary cholesterol concentration and secretion rates (1.5-fold and 1.9-fold, respectively), resulting in 1.6-fold increased fecal cholesterol excretion, decreased hepatic cholesterol, and increased (4.4-fold) de novo hepatic cholesterol synthesis versus LDLr-KO mice. Plasma lipids decreased (total cholesterol, 32%; cholesteryl ester, 32%; free cholesterol, 30%), mostly as a result of reduced non-high density lipoprotein-cholesterol and apolipoprotein B (apoB; 36% and 25%, respectively). ApoB-containing lipoproteins were smaller and lipid-depleted in ABCG5/ G8-Tg3LDLr-KO mice. Kinetic studies revealed similar 125 I-apoB intermediate density lipoprotein/LDL fractional catabolic rates, but apoB production rates were decreased 37% in ABCG5/G8-Tg3LDLr-KO mice. Proximal aortic atherosclerosis decreased by 52% (male) and 59% (female) in ABCG5/G8-Tg3LDLr-KO versus LDLr-KO mice fed the Western/ezetimibe diet. Thus, increased biliary secretion, resulting from hepatic ABCG5/G8 overexpression, reduces atherogenic risk in LDLr-KO mice fed a Western diet containing ezetimibe. These findings identify distinct roles for liver and intestinal ABCG5/G8 in modulating sterol metabolism and

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Section: Discussionmentioning

confidence: 80%

Hepatic ABCG5/G8 overexpression reduces apoB-lipoproteins and atherosclerosis when cholesterol absorption is inhibited

Basso

Freeman

et al. 2007

Journal of Lipid Research

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“…Secretory control via PERPP/autophagosomes likely represents a key component of normal and pathologic regulation of plasma apoB levels, given that PUFAs are a major component of the hearthealthy lifestyle owing to their lipid-lowering properties (40) and that many diseases of apoB oversecretion have become a major health problem (6).…”

Section: Discussionmentioning

confidence: 99%

“…Retention, or trapping, of apoB-lipoproteins within the arterial wall is the key initiating event in the pathogenesis of atherosclerosis, the major cause of death world-wide (2-4). Thus, apoB-lipoprotein assembly and secretion, which are often dysregulated (5,6), attract considerable interest.…”

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confidence: 99%

Presecretory oxidation, aggregation, and autophagic destruction of apoprotein-B: A pathway for late-stage quality control

Pan

Maitin

Parathath

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

121

108

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Hepatic secretion of apolipoprotein-B (apoB), the major protein of atherogenic lipoproteins, is regulated through posttranslational degradation. We reported a degradation pathway, post-ER presecretory proteolysis (PERPP), that is increased by reactive oxygen species (ROS) generated within hepatocytes from dietary polyunsaturated fatty acids (PUFA). We now report the molecular processes by which PUFA-derived ROS regulate PERPP of apoB. ApoB exits the ER; undergoes limited oxidant-dependent aggregation; and then, upon exit from the Golgi, becomes extensively oxidized and converted into large aggregates. The aggregates slowly degrade by an autophagic process. None of the oxidized, aggregated material leaves cells, thereby preventing export of apoBlipoproteins containing potentially toxic lipid peroxides. In summary, apoB secretory control via PERPP/autophagosomes is likely a key component of normal and pathologic regulation of plasma apoB levels, as well as a means for remarkably late-stage quality control of a secreted protein.

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“…In addition to the design and modeling aspects of lipoprotein kinetics studies, what we have learned from apolipoprotein B (apoB) and HDL apoA-I and apoA-II tracer kinetics studies is covered in the present series of reviews by Parhofer and Barrett (1) and Rashid, Patterson, and Lewis (2). Other recent reviews of the present field of investigation and its applications include those by Marsh et al (3,4) and Barrett, and Watts (5).…”

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confidence: 99%

Thematic review series: Patient-Oriented Research. Design and analysis of lipoprotein tracer kinetics studies in humans

Barrett

Chan

Watts

2006

Journal of Lipid Research

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Lipoprotein tracer kinetics studies have for many years provided new and important knowledge of the metabolism of lipoproteins. Our understanding of kinetics defects in lipoprotein metabolism has resulted from the use of tracer kinetics studies and mathematical modeling. This review discusses all aspects of the performance of kinetics studies, including the development of hypotheses, experimental design, statistical considerations, tracer administration and sampling schedule, and the development of compartmental models for the interpretation of tracer data. In addition to providing insight into new metabolic pathways, such models provide quantitative information on the effect of interventions on lipoprotein metabolism. Compartment models are useful tools to describe experimental data but can also be used to aid in experimental design and hypothesis generation. The SAAM II program provides an easy-to-use interface with which to develop and test compartmental models against experimental models. The development of a model requires that certain checks be performed to ensure that the model describes the experimental data and that the model parameters can be estimated with precision.In addition to methodologic aspects, several compartment models of apoprotein and lipid metabolism are reviewed. Years of clinical investigation have provided valuable insight into the complexity of human lipoprotein metabolism. The measurement of plasma lipoprotein concentrations provides useful information, but from a functional viewpoint these concentrations reflect the balance between input and output in the lipoprotein system in plasma. The only way to quantify input and output in this system is by undertaking kinetics studies, typically using tracer methodology. These studies, however, are time-consuming and difficult to perform. Nevertheless, they are important to characterize the pathways that result in dyslipidemic states and to describe the in vivo mechanisms of action of treatments designed to regulate dyslipidemia and cardiovascular disease risk in clinical practice. There are many steps to consider when planning such metabolic studies. This review touches on all aspects of the design and analysis of lipoprotein kinetics studies, including philosophical angles, tracer methodology, mathematical modeling, and statistical considerations related to experimental design and analysis.With the advent of commercial stable isotopes and endogenous labeling protocols, some aspects of performing kinetics studies are now easier than when radioactive tracers and laborious exogenous labeling of lipoproteins were required. However, the number of laboratories and research groups undertaking these types of metabolic studies has changed little, highlighting the complexity of the methods involved.In addition to the design and modeling aspects of lipoprotein kinetics studies, what we have learned from apolipoprotein B (apoB) and HDL apoA-I and apoA-II tracer kinetics studies is covered in the present series of reviews by Parhofer and Barret...

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Thematic review series: Patient-Oriented Research. What we have learned about VLDL and LDL metabolism from human kinetics studies

Cited by 51 publications

References 106 publications

Hepatic ABCG5/G8 overexpression reduces apoB-lipoproteins and atherosclerosis when cholesterol absorption is inhibited

Hepatic ABCG5/G8 overexpression reduces apoB-lipoproteins and atherosclerosis when cholesterol absorption is inhibited

Presecretory oxidation, aggregation, and autophagic destruction of apoprotein-B: A pathway for late-stage quality control

Thematic review series: Patient-Oriented Research. Design and analysis of lipoprotein tracer kinetics studies in humans

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