Phospholipid transfer protein: its impact on lipoprotein homeostasis and atherosclerosis

Jiang, Xian‐Cheng

doi:10.1194/jlr.r082503

Cited by 31 publications

(24 citation statements)

References 109 publications

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“…In addition to isolating APOA1-HDL, enrichment of PLTP-containing HDL particles may be necessary to detect APOA1 transfer from alpha2 to alpha1 and alpha0. It is also possible that PLTP’s primary function on HDL in plasma is not its phospholipid transfer activity, which is localized to its minor alpha2 size ( 30 , 39 ), but instead a currently unidentified function in alpha0 and alpha1 ( 41 ). Alpha0 and alpha1 contain the majority of PLTP mass on HDL (60%) and a higher ratio of PLTP per particle (1 molecule of PLTP for every 20 and 50 particles of alpha0 and alpha1, respectively), compared with alpha2 (36% of total PLTP mass on HDL, 1 molecule of PLTP for every 500 alpha2 particles).…”

Section: Discussionmentioning

confidence: 99%

Metabolism of PLTP, CETP, and LCAT on multiple HDL sizes using the Orbitrap Fusion Lumos

Singh¹,

Andraski²,

Higashi³

et al. 2021

JCI Insight

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Recent in vivo tracer studies demonstrated that targeted mass spectrometry (MS) on the Q Exactive Orbitrap could determine the metabolism of HDL proteins 100s-fold less abundant than apolipoprotein A1 (APOA1). In this study, we demonstrate that the Orbitrap Lumos can measure tracer in proteins whose abundances are 1000s-fold less than APOA1, specifically the lipid transfer proteins phospholipid transfer protein (PLTP), cholesterol ester transfer protein (CETP), and lecithin-cholesterol acyl transferase (LCAT). Relative to the Q Exactive, the Lumos improved tracer detection by reducing tracer enrichment compression, thereby providing consistent enrichment data across multiple HDL sizes from 6 participants. We determined by compartmental modeling that PLTP is secreted in medium and large HDL (alpha2, alpha1, and alpha0) and is transferred from medium to larger sizes during circulation from where it is catabolized. CETP is secreted mainly in alpha1 and alpha2 and remains in these sizes during circulation. LCAT is secreted mainly in medium and small HDL (alpha2, alpha3, prebeta). Unlike PLTP and CETP, LCAT’s appearance on HDL is markedly delayed, indicating that LCAT may reside for a time outside of systemic circulation before attaching to HDL in plasma. The determination of these lipid transfer proteins’ unique metabolic structures was possible due to advances in MS technologies.

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Section: Discussionmentioning

confidence: 99%

Metabolism of PLTP, CETP, and LCAT on multiple HDL sizes using the Orbitrap Fusion Lumos

Singh¹,

Andraski²,

Higashi³

et al. 2021

JCI Insight

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“…On the other hand, the effect of PLTP inhibition on RCT is currently controversial. 5 It has been suggested that just increasing the total amounts of HDL would not directly lead to the treatment of dyslipidemia and cardiovascular diseases. 22,23 Therefore, we postulate that investigation using PLTP inhibitors with a higher affinity and inhibitory activity may resolve the issue of whether a change of HDL metabolism by PLTP inhibition would contribute to the treatment of the above-mentioned diseases.…”

Section: Discussionmentioning

confidence: 99%

“…4 PLTP is ubiquitously expressed in animal cells and tissues with higher expression in macrophages and atherosclerotic lesions, and its expression in the liver accounts for around 25% of all plasma PLTP activity. 5 Its expression can be regulated by transcription factors such as peroxisome proliferator-activated receptor, 6 farnesoid X receptor, 7 liver X receptor, 8,9 and sterol regulatory element-binding protein 1c, 10 which are involved in lipid synthesis, lipoprotein production, and reverse cholesterol transport (RCT). In addition, a hyperlipidemia mouse model induced by a high-fat, high-cholesterol diet exhibited a significant increase in PLTP expression and activity.…”

Section: Introductionmentioning

confidence: 99%

Identification of Novel Phospholipid Transfer Protein Inhibitors by High-Throughput Screening

et al. 2019

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Atherogenesis has been recognized as a risk factor for lethal cardiovascular diseases. Plasma low-density lipoprotein levels are correlated to the occurrence of atherosclerosis, and their control is critical for both the prevention and treatment of these diseases. Phospholipid transfer protein (PLTP) is one of the key regulators of lipoprotein metabolism; PLTP-deficient mice exhibit decreased apolipoprotein B (apoB)-containing lipoprotein secretion and atherosclerosis, indicating the validity of PLTP as a promising therapeutic target. Here, we demonstrate a high-throughput screening (HTS) method to identify a novel chemotype of PLTP inhibitors. Instead of using recombinant proteins, we used human plasma as a source of enzymes in the first screening, so as to efficiently exclude promiscuous inhibitors. The selected compounds were further confirmed to target PLTP both biochemically and biophysically and were shown to inhibit apoB secretion from hepatic cells with no apparent toxicity. We believe that our approach is suitable for filtering out nonspecific inhibitors at an earlier stage of screening campaigns and that these compounds should have potential to be developed into drugs to treat dyslipidemia.

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“…FFA taken up by the liver could also be re-esterified into triglycerides. While we did not find liver triglyceride levels to be different, the increased abundance of Pltp mRNA in sedentary and exercised vitamin-E fed mice may be of interest in this context; Pltp is a vitamin E transfer protein and is also important for the lipidation and hepatic secretion of VLDL [ 34 ]. Thus, the vitamin E-supplemented mice may not have accumulated hepatic triglycerides due to increased VLDL release.…”

Section: Discussionmentioning

confidence: 99%

A Vitamin E-Enriched Antioxidant Diet Interferes with the Acute Adaptation of the Liver to Physical Exercise in Mice

Hoene¹,

Irmler

Beckers

et al. 2018

Nutrients

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Physical exercise is beneficial for general health and is an effective treatment for metabolic disorders. Vitamin E is widely used as dietary supplement and is considered to improve non-alcoholic fatty liver disease by reducing inflammation and dyslipidemia. However, increased vitamin E intake may interfere with adaptation to exercise training. Here, we explored how vitamin E alters the acute exercise response of the liver, an organ that plays an essential metabolic role during physical activity. Mice fed a control or an α-tocopherol-enriched diet were subjected to a non-exhaustive treadmill run. We assessed the acute transcriptional response of the liver as well as glucocorticoid signalling and plasma free fatty acids (FFA) and performed indirect calorimetry. Vitamin E interfered with the exercise-induced increase in FFA and upregulation of hepatic metabolic regulators, and it shifted the transcriptional profile of exercised mice towards lipid and cholesterol synthesis while reducing inflammation. Energy utilization, as well as corticosterone levels and signalling were similar, arguing against acute differences in substrate oxidation or glucocorticoid action. Our results show that high-dose vitamin E alters the metabolic and inflammatory response of the liver to physical exercise. The interference with these processes may suggest a cautious use of vitamin E as dietary supplement.

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Phospholipid transfer protein: its impact on lipoprotein homeostasis and atherosclerosis

Cited by 31 publications

References 109 publications

Metabolism of PLTP, CETP, and LCAT on multiple HDL sizes using the Orbitrap Fusion Lumos

Metabolism of PLTP, CETP, and LCAT on multiple HDL sizes using the Orbitrap Fusion Lumos

Identification of Novel Phospholipid Transfer Protein Inhibitors by High-Throughput Screening

A Vitamin E-Enriched Antioxidant Diet Interferes with the Acute Adaptation of the Liver to Physical Exercise in Mice

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