scholarly journals Liver phospholipid transfer protein (PLTP) expression with a PLTP-null background promotes very low-density lipoprotein production in mice

Hepatology ◽  
2012 ◽  
Vol 56 (2) ◽  
pp. 576-584 ◽  
Author(s):  
Amirfarbod Yazdanyar ◽  
Xian-Cheng Jiang
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Liver Phospholipid ◽  
Phospholipid Transfer Protein ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Transfer Protein ◽  
Phospholipid Transfer

scholarly journals miR-130b is a potent stimulator of hepatic very-low-density lipoprotein assembly and secretion via marked induction of microsomal triglyceride transfer protein

2020 ◽  
Vol 318 (2) ◽  
pp. E262-E275 ◽  
Author(s):  
Jing Zhang ◽  
Ferdous Rastgar Jazii ◽  
Mahdi Montazer Haghighi ◽  
Danielle Alvares ◽  
Lipei Liu ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Hepg2 Cells ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Microsomal Triglyceride Transfer Protein ◽  
Luciferase Reporter ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Transfer Protein ◽  
Stimulation Of

miR-130b is a microRNA whose expression is particularly elevated within adipose tissue and in the circulation in diabetic states. Hepatic miR-130b expression has been linked to hepatocellular carcinoma and changes in lipid metabolism. Here, we investigated the role of miR-130b in hepatic lipid homeostasis and lipoprotein export. We observed that overexpression of miR-130b-3p or -5p in HepG2 cells markedly enhanced the secretion of very-low-density lipoprotein (VLDL) particles, enhanced the secretion of [3H]glycerol metabolically labeled triglyceride (TG), and significantly increased the number or the average size of lipid droplets (LDs), respectively. Overexpression of miR-130b also altered the expression of key genes involved in lipid metabolism and in particular markedly increased both mRNA and protein expression levels of microsomal triglyceride transfer protein (MTP). Conversely, the miR-130b inhibitor decreased mRNA levels of MTP and fatty acid synthase ( FAS) in HepG2 cells. However, dual-luciferase reporter assays indicated that MTP is not a direct target of miR-130b-3p. miR-130b overexpression did not alter de novo synthesized TG or the stability and secretion of apolipoprotein B 100. Interestingly, knockdown of phosphatase and tensin homolog ( PTEN) blocked the upregulation of MTP mRNA induced by miR-130b. Finally, miR-130b-induced stimulation of VLDL secretion was also observed in a second hepatocyte cell culture model, immortalized human hepatocytes, confirming the effects observed in HepG2 cells. Overall, these data suggest a potential role for miR-130b in promoting hepatic VLDL assembly and secretion mediated by marked stimulation of MTP expression and TG mobilization. Thus miR-130b overexpression corrects the defect in VLDL production in HepG2 cells.

scholarly journals Microsomal triglyceride transfer protein activity remains unchanged in rat livers under conditions of altered very-low-density lipoprotein secretion

1995 ◽  
Vol 310 (1) ◽  
pp. 11-14 ◽  
Author(s):  
D J Brett ◽  
R J Pease ◽  
J Scott ◽  
G F Gibbons
Keyword(s):  
Cultured Cells ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Microsomal Triglyceride Transfer Protein ◽  
Autosomal Recessive Disorder ◽  
Diabetic Rat ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Protein Activity ◽  
Transfer Protein

Microsomal triglyceride transfer protein (MTP) is a heterodimeric protein consisting of a unique 97 kDa subunit and protein disulphide isomerase, that mediates the transfer of lipid between membranes and nascent lipoproteins. Mutations in the gene encoding the 97 kDa subunit of the protein cause the rare autosomal recessive disorder abetalipoproteinaemia. Recent findings in cultured cells indicate that the 5′ promoter region contains an insulin-responsive element, suggesting that the gene is responsive to insulin regulation. In this study we examined two cases where very-low-density lipoprotein (VLDL) secretion is markedly reduced: the streptozotocin-diabetic rat and 10-day-old suckling rats. In both cases MTP activity was unaltered compared with that in control animals. Equal levels of MTP were also apparent in the livers of all groups of animals, as measured by immunoblotting with an anti-MTP antiserum. These findings indicate that factors other than MTP activity are responsible for the reduction in hepatic VLDL triglyceride secretion observed in the suckling and diabetic animals.

scholarly journals Bexarotene Induces Dyslipidemia by Increased Very Low-Density Lipoprotein Production and Cholesteryl Ester Transfer Protein-Mediated Reduction of High-Density Lipoprotein

Endocrinology ◽  
2009 ◽  
Vol 150 (5) ◽  
pp. 2368-2375 ◽  
Author(s):  
Jitske de Vries-van der Weij ◽  
Willeke de Haan ◽  
Lihui Hu ◽  
Maarten Kuif ◽  
H. Ling D. W. Oei ◽  
...  
Keyword(s):  
Thyroid Carcinoma ◽  
High Density Lipoprotein ◽  
Cholesteryl Ester ◽  
Cholesteryl Ester Transfer Protein ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Differentiated Thyroid Carcinoma ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Transfer Protein

A common dose-limiting side effect of treatment with the retinoid X receptor agonist bexarotene is dyslipidemia. We evaluated the effects of bexarotene on plasma lipid metabolism in patients with metastatic differentiated thyroid carcinoma and investigated the underlying mechanism(s) in apolipoprotein (APO) E*3-Leiden mice without (E3L) and with human cholesteryl ester transfer protein (CETP; E3L.CETP). To this end, 10 patients with metastatic differentiated thyroid carcinoma were treated with bexarotene (300 mg/d) for 6 wk. Bexarotene increased plasma triglyceride (TG; +150%), primarily associated with very low-density lipoprotein (VLDL), and raised plasma total cholesterol (+50%). However, whereas bexarotene increased VLDL-cholesterol (C) and low-density lipoprotein (LDL)-C (+63%), it decreased high-density lipoprotein (HDL)-C (−30%) and tended to decrease apoAI (−18%) concomitant with an increase in endogenous CETP activity (+44%). To evaluate the cause of the bexarotene-induced hypertriglyceridemia and the role of CETP in the bexarotene-induced shift in cholesterol distribution, E3L and E3L.CETP mice were treated with bexarotene through dietary supplementation [0.03% (wt/wt)]. Bexarotene increased VLDL-associated TG in both E3L (+47%) and E3L.CETP (+29%) mice by increasing VLDL-TG production (+68%). Bexarotene did not affect the total cholesterol levels or distribution in E3L mice but increased VLDL-C (+11%) and decreased HDL-C (−56%) as well as apoAI (−31%) in E3L.CETP mice, concomitant with increased endogenous CETP activity (+41%). This increased CETP activity by bexarotene-treatment is likely due to the increase in VLDL-TG, a CETP substrate that drives CETP activity. In conclusion, bexarotene causes combined dyslipidemia as reflected by increased TG, VLDL-C, and LDL-C and decreased HDL-C, which is the result of an increased VLDL-TG production that causes an increase of the endogenous CETP activity.

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

2019 ◽  
Vol 24 (5) ◽  
pp. 579-586
Author(s):  
Rie Hantani ◽  
Yu Takahashi ◽  
Tomohiro Sotani ◽  
Yoshiji Hantani
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Low Density Lipoprotein ◽  
Lipoprotein Metabolism ◽  
Density Lipoprotein ◽  
Phospholipid Transfer Protein ◽  
Transfer Protein ◽  
Hepatic Cells ◽  
Promising Therapeutic Target ◽  
Phospholipid Transfer

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.

scholarly journals Phospholipid transfer protein activity in two cholestatic patients

2004 ◽  
Vol 122 (4) ◽  
pp. 175-177 ◽  
Author(s):  
Eliana Cotta de Faria ◽  
Adriana Celeste Gebrin ◽  
Wilson Nadruz Júnior ◽  
Lucia Nassi Castilho
Keyword(s):  
Density Lipoprotein ◽  
Plasma Phospholipid ◽  
Low Density Lipoproteins ◽  
High Density ◽  
High Density Lipoproteins ◽  
Phospholipid Transfer Protein ◽  
Low Density ◽  
Protein Activity ◽  
Transfer Protein ◽  
Phospholipid Transfer

CONTEXT: Plasma phospholipid transfer protein mediates the transfer of phospholipids from triglyceride-rich lipoproteins, very low density lipoproteins and low density lipoproteins to high density lipoproteins, a process that is also efficient between high density lipoprotein particles. It promotes a net movement of phospholipids, thereby generating small lipid-poor apolipoprotein AI that contains particles and subfractions that are good acceptors for cell cholesterol efflux. CASE REPORT: We measured the activity of plasma phospholipid transfer protein in two cholestatic patients, assuming that changes in activity would occur in serum that was positive for lipoprotein X. Both patients presented severe hypercholesterolemia, high levels of low density lipoprotein cholesterol and, in one case, low levels of high density lipoprotein cholesterol and high levels of phospholipid serum. The phospholipid transfer activity was close to the lower limit of the reference interval. To our knowledge, this is the first time such results have been presented. We propose that phospholipid transfer protein activity becomes reduced under cholestasis conditions because of changes in the chemical composition of high density lipoproteins, such as an increase in phospholipids content. Also, lipoprotein X, which is rich in phospholipids, could compete with high density lipoproteins as a substrate for phospholipid transfer protein.

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