ApoO, a Novel Apolipoprotein, Is an Original Glycoprotein Up-regulated by Diabetes in Human Heart

Lamant, Matthieu; Smih, Fatima; Harmancey, Romain; Philip-Couderc, Pierre; Pathak, Atul; Roncalli, Jérôme; Galinier, Michel; Collet, Xavier; Massabuau, P; Senard, Jean‐Michel; Rouet, Philippe

doi:10.1074/jbc.m510861200

Cited by 77 publications

(95 citation statements)

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“…This may be the pool of CETP we determined to be cytosolic in cell fractionation studies. Although the mechanism for CETP release into the cytoplasm is unknown, the escape of other endoplasmic reticulum luminal proteins to the cytoplasm has been reported (51)(52)(53). Notably, just like CETP, several of these proteins bind to plasma lipoproteins.…”

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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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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“…ApoO, a minor HDL component expressed in several human tissues (Lamant et al 2006), is present in HDL, LDL and VLDL, belongs to the proteoglycan family and contains chondroitin sulphate chains, a unique feature distinguishing it from other apolipoproteins. The physiological function of apoO remains unknown (Nijstad et al 2011).…”

Section: Apolipoproteinsmentioning

confidence: 99%

Structure of HDL: Particle Subclasses and Molecular Components

Kontush

Lindahl

Lhomme

et al. 2014

Handbook of Experimental Pharmacology

228

226

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“…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).…”

mentioning

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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ApoO, a Novel Apolipoprotein, Is an Original Glycoprotein Up-regulated by Diabetes in Human Heart

Cited by 77 publications

References 73 publications

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

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

Structure of HDL: Particle Subclasses and Molecular Components

Defective triglyceride biosynthesis in CETP-deficient SW872 cells

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