Preferential expression of cholesteryl ester transfer protein mRNA by stromal-vascular cells of human adipose tissue

Radeau, Thierry; Robb, Malcolm; McDonnell, Michael; McPherson, Ruth

doi:10.1016/s0005-2760(98)00039-3

Cited by 17 publications

(11 citation statements)

References 32 publications

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“…Also, fat cell number increases in adult life in severe human obesity. The studies of Gauthier et al 27 and Radeau et al 28 suggest that CETP levels might be increased in neonates and in children undergoing rapid weight gain. On the other hand, early differentiation markers can be detected even in adipose tissue derived from very old mice.…”

Section: Discussionmentioning

confidence: 99%

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Relationship Between Cholesteryl Ester Transfer Protein and Atherogenic Lipoprotein Profile in Morbidly Obese Women

Ebenbichler

Laimer

Kaser

et al. 2002

ATVB

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Objective-Obesity is associated with increased morbidity and mortality from atherosclerotic disease. Lipid abnormalities contribute to the increased relative risk in obese subjects. Cholesteryl ester transfer protein (CETP) mass is increased in these patients and might mediate the atherogenic lipoprotein pattern observed in obesity. Methods and Results-Twenty-one morbidly obese, middle-aged, female subjects participated in this prospective study.Subjects were examined before and 1 year after surgical treatment. Fat mass was determined by body impedance analysis; CETP mass, by ELISA; CETP activity, by exogenous substrate assay; and LDL particle diameter, by gradient gel electrophoresis. Mean weight loss after 1 year was 28.7 kg; mean fat mass loss was 22.6 kg. Mean CETP mass decreased from 1.81 to 1.32 g/mL (Pϭ0.008); mean CETP activity decreased from 244 to 184 nmol · mL Ϫ1 · h Ϫ1 (Pϭ0.004); and in parallel, the mean diameter of LDL particles increased (256.8 to 258.4 Å, Pϭ0.04). Conclusions-We conclude that weight loss is associated with a pronounced decrease in CETP mass and activity and a consistent increase in LDL particle diameter. After 1 year of this prospective study in morbidly obese subjects undergoing weight loss by surgical treatment, it has been determined that some features of the atherogenic lipoprotein profile can be reversed. O besity is linked to a variety of metabolic and hormonal dysfunctions, such as the development of insulin resistance and dyslipidemia, leading to increased morbidity and mortality in these subjects. 1 Adipose tissue is not solely an energy storage tissue but is also involved in metabolic processes expressing and secreting bioactive compounds, such as cholesteryl ester transfer protein (CETP) and leptin.Obesity is associated with dyslipidemia, elevated triglyceride (TG) levels, low HDL cholesterol (HDL-C) levels, and small dense LDL particles. These alterations in plasma lipoprotein metabolism have been shown to increase the risk of cardiovascular disease in men and women. 2 The state of dyslipidemia is also influenced by body fat distribution. Abdominal obesity is linked to a higher risk profile for cardiovascular disease. 3 Adipose tissue is a prominent source of CETP. 4 CETP is an important determinant of lipoprotein composition because of its capacity to mediate the transfer of cholesteryl esters (CEs) from CE-rich lipoproteins to TG-rich lipoproteins in exchange for TGs. 5,6 In obese subjects, CETP activity and mass were increased, whereas lipoprotein lipase (LPL) activity after heparin administration was significantly decreased. 7 LDL particles vary in size, density, and composition. LDL particles can be classified into 2 LDL subclass patterns: pattern A describes the preponderance of large LDL particles, whereas small dense LDL particles are defined as pattern B. In several epidemiological studies, the presence of small dense LDL particles has been linked to atherosclerotic diseases. Several cellular and molecular mechanisms have been implicated in the higher atherog...

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Section: Discussionmentioning

confidence: 99%

“…27 CETP mRNA is most highly expressed in immature fat cells of the human adipose tissue. 28 White adipose tissue formation begins before birth, and expansion takes place rapidly after birth as a result of increased fat cell size as well as fat cell number. Also, fat cell number increases in adult life in severe human obesity.…”

Section: Discussionmentioning

confidence: 99%

Relationship Between Cholesteryl Ester Transfer Protein and Atherogenic Lipoprotein Profile in Morbidly Obese Women

Ebenbichler

Laimer

Kaser

et al. 2002

ATVB

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“…In human adipocytes, CETP expression is also induced during this differentiation process ( 48,49 ). CETP expression is highest in small lipid-poor adipocytes, and then decreases when fat cells become TG-fi lled ( 48,50 ). The timing of these events suggests that CETP may have a role in lipid storage.…”

Section: Discussionmentioning

confidence: 99%

“…The expression of both CETP and apoE is induced during adipocyte development ( 48,60 ). For both proteins, expression is closely linked to cellular TG and cholesterol content ( 50,60 ).…”

Section: Discussionmentioning

confidence: 99%

Defective triglyceride biosynthesis in CETP-deficient SW872 cells

Greene

Izem

Morton

2015

Journal of Lipid Research

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with adipose tissue CETP mRNA levels in both man and hamster ( 6,7 ), showing the importance of this tissue in both lipid storage and the modulation of intravascular lipid metabolism.While most CETP is secreted by cells, a portion is retained ( 8-10 ). Much of the intracellular CETP pool is associated with the endoplasmic reticulum (ER), with increased concentrations near lipid droplets ( 8,11 ). Both cytoplasmic and lipid-droplet pools of CETP have been observed as well ( 11 ). Although the mechanism for CETP release into the cytoplasm is unknown, the escape of other ER luminal proteins to the cytoplasm has been reported (12)(13)(14).In addition to its role in plasma lipoprotein metabolism, multiple studies suggest that CETP has other functions. Cell-associated CETP promotes CE uptake from HDL, stimulates the cell's ability to effl ux cholesterol, and infl uences the storage of CE in cells (15)(16)(17)(18)(19). In addition to altering cellular cholesterol metabolism, both overexpression and under-expression of CETP in SW872 cells, a human cell line commonly used as an adipocyte model, reduce the capacity of these cells to store TG ( 10, 11 ). A role for CETP in adipocyte lipid storage is further supported by observations in transgenic mice. Adipose tissue-specifi c expression of human CETP in mice results in smaller adipocytes containing less TG and cholesterol, and signifi cantly reduces the expression of key lipogenic genes ( 20 ). In hypertriglyceridemic mice, CETP expression normalizes subcutaneous adipose depots and visceral adipocyte size ( 21 ). And in humans, a CETP gene variant that affects the coding sequence of CETP is associated with increased adiposity following long-term overfeeding ( 22 ).In this study, we have examined pathways involved in TG homeostasis in order to understand the metabolic Abstract We previously reported that reducing the expression of cholesteryl ester transfer protein (CETP) disrupts cholesterol homeostasis in SW872 cells and causes an ‫ف‬ 50% reduction in TG. The causes of this reduced TG content, investigated here, could not be attributed to changes in the differentiation status of CETP-defi cient cells, nor was there evidence of endoplasmic reticulum (ER) stress. In short-term studies, the total fl ux of oleate through the TG biosynthetic pathway was not altered in CETP-defi cient cells, although mRNA levels of some pathway enzymes were different. However, the conversion of diglyceride (DG) to TG was impaired. In longer-term studies, newly synthesized TG was not effectively transported to lipid droplets, yet this lipid did not accumulate in the ER, apparently due to elevated lipase activity in this organelle. DG, shown to be a novel CETP substrate, was also ineffi ciently transferred to lipid droplets. This may reduce TG synthesis on droplets by resident diacylglycerol acyltransferase. Overall, these data suggest that the decreased TG content of CETP-defi cient cells arises from the reduced conversion of DG to TG in the ER and/or on the lipid droplet surface, and enhanced ...

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“…CETP expression is upregulated early in adipocyte development ( 54,55 ). Additionally, the relative abundance of full-length and exon 9-deleted CETP mRNAs is variable and tissue specifi c ( 6 ).…”

Section: Note Added In Proofmentioning

confidence: 99%

Overexpression of full-length cholesteryl ester transfer protein in SW872 cells reduces lipid accumulation

Izem

Greene

Białkowska

et al. 2015

Journal of Lipid Research

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CETP is also present inside cells where two isoforms exist: full-length CETP, which is equivalent to plasma CETP, and exon 9-deleted CETP, a smaller form derived from alternatively spliced mRNA ( 6 ). The function of exon 9-deleted CETP is poorly understood. Overexpression studies suggest that exon 9-deleted CETP may bind to full-length CETP and hinder its secretion ( 6, 7 ), although this role was not supported by subsequent transgenic mouse studies ( 8 ).Multiple studies suggest that intracellular CETP modulates lipid metabolism. Cell-associated CETP promotes CE uptake from HDL, stimulates the cell's ability to effl ux cholesterol, and infl uences the storage of CE in cells ( 9-12 ). Acute suppression of CETP biosynthesis by antisense oligonucleotides in SW872 cells reduces cholesterol synthesis and increases CE accumulation ( 13 ). SW872 cells chronically defi cient in CETP manifest more profound alterations in lipid metabolism including reduced capacity to store TG ( 14 ). A role for CETP in cellular lipid storage is further supported by observations in transgenic mice. Adipose tissue-specifi c expression of human CETP in mice results in smaller adipocytes containing less TG and cholesterol and signifi cantly reduces the expression of key lipogenic genes ( 15 ). In hypertriglyceridemic mice, CETP expression normalizes subcutaneous adipose depots and visceral adipocyte size ( 16 ). And in humans, a CETP gene variant that affects the coding sequence of both full-length and exon 9-deleted CETP is associated with increased adiposity following long-term overfeeding ( 17 ).Our initial studies in intracellular CETP, which used a molecular approach that reduced both full-length and exon 9-deleted CETP expression, identifi ed multiple aberrations in lipid metabolism and storage ( 13,14 ). In that Abstract Cells produce two cholesteryl ester transfer protein (CETP) isoforms, full-length and a shorter variant produced by alternative splicing. Blocking synthesis of both isoforms disrupts lipid metabolism and storage. To further defi ne the role of CETP in cellular lipid metabolism, we stably overexpressed full-length CETP in SW872 cells. These CETP + cells had several-fold higher intracellular CETP and accumulated 50% less TG due to a 26% decrease in TG synthesis and 2.5-fold higher TG turnover rate. Reduced TG synthesis was due to decreased fatty acid uptake and impaired conversion of diglyceride to TG even though diacylglycerol acyltransferase activity was normal. Sterol-regulatory element binding protein 1 mRNA levels were normal, and although PPAR ␥ expression was reduced, the expression of several of its target genes including adipocyte triglyceride lipase, FASN , and APOE was normal. In cells, multiple proteins transport phospholipids, sterols, and fatty acids between organelles ( 1, 2 ). However, little is known about the molecular mechanisms of cholesteryl ester (CE) and TG transport. A candidate protein for this function is cholesteryl ester transfer protein (CETP). CETP's role in CE and TG transport in plasma ...

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Preferential expression of cholesteryl ester transfer protein mRNA by stromal-vascular cells of human adipose tissue

Cited by 17 publications

References 32 publications

Relationship Between Cholesteryl Ester Transfer Protein and Atherogenic Lipoprotein Profile in Morbidly Obese Women

Relationship Between Cholesteryl Ester Transfer Protein and Atherogenic Lipoprotein Profile in Morbidly Obese Women

Defective triglyceride biosynthesis in CETP-deficient SW872 cells

Overexpression of full-length cholesteryl ester transfer protein in SW872 cells reduces lipid accumulation

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