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

Izem, Lahoucine; Greene, Diane J.; Białkowska, Katarzyna; Morton, Richard E.

doi:10.1194/jlr.m053678

Cited by 17 publications

(38 citation statements)

References 58 publications

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“…Interestingly, in preliminary studies, we observed that APOE mRNA levels in CETP-defi cient cells are only 5% of control levels. In contrast, cells overexpressing CETP, which also have decreased TG storage capacity, have normal APOE expression ( 11 ). It remains to be determined how suppressing CETP expression leads to reduced APOE expression, and whether a portion of the low TG phenotype in CETP-defi cient cells can be rescued by normalizing APOE expression.…”

Section: Discussionmentioning

confidence: 96%

“…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).…”

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confidence: 99%

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confidence: 99%

“…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.…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 96%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Defective triglyceride biosynthesis in CETP-deficient SW872 cells

Greene

Izem

Morton

2015

Journal of Lipid Research

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“…Androgen receptors are widely expressed in the Hd of zebrafish 27 , comparable to bpifcl expression identified in this study; this strongly suggests that testosterone could regulate Bpifcl modulation of kiss2 mRNA expression in the Hd of females. The BPIF family is known as a secreted protein 3 , 5 – 10 , however, several genes such as CETP 28 and PLTP 29 are also expressed in cytoplasm and nucleus. Especially, PLTP is suggested to be a modulator of signal transduction of the activation of the phosphatidylinositol-3 kinase/Akt pathway 29 .…”

Section: Discussionmentioning

confidence: 99%

Bpifcl modulates kiss2 expression under the influence of 11-ketotestosterone in female zebrafish

Moriya

Tahsin

Parhar

2017

Sci Rep

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The bactericidal/permeability-increasing (BPI) fold-containing (BPIF) superfamily of genes expressed in the brain are purportedly involved in modulating brain function in response to stress, such as inflammation. Kisspeptin, encoded by kiss, is affected by inflammation in the brain; therefore, BPIF family genes might be involved in the modulation of kisspeptin in the brain. In this study, we investigated the expression of BPIF family C, like (bpifcl) in zebrafish brain and its involvement in kiss2 regulation. The identified, full-length sequence of a bpifcl isoform expressed in the zebrafish brain contained the BPI fold shared by BPIF family members. bpifcl mRNA expression in female zebrafish brains was significantly higher than that in males. Exposure of female zebrafish to 11-ketotestosterone decreased bpifcl and kiss2 mRNA expression. bpifcl knockdown by bpifcl-specific small interfering RNA administration to female zebrafish brain decreased kiss2 mRNA expression. bpifcl expression was widely distributed in the brain, including in the dorsal zone of the periventricular hypothalamus (Hd). Furthermore, bpifcl was also expressed in KISS2 neurons in the Hd. These results suggest that the Bpifcl modulates kiss2 mRNA expression under the influence of testosterone in the Hd of female zebrafish.The bactericidal/permeability-increasing (BPI) fold-containing (BPIF) superfamily of genes is functionally classified into five groups: palate, lung and nasal epithelium clone (PLUNC); lipopolysaccharide-binding protein (LBP); BPI protein; phospholipid transfer protein (PLTP); cholesterol ester transfer protein (CETP) 1, 2 . All BPIF family members share the BPI fold, which has an elongated, boomerang shape consisting of two distinct N-and C-terminal domain barrels with a highly similar secondary structure 3 . Both domains consist of two twisted, anti-parallel β-sheets and two α-helices, with both domains connected to each other by a β-sheet 4 .BPIF family of genes are expressed in a wide range of vertebrates 5 and mainly involved in the innate immune system and lipoprotein metabolism. BPI and LBP are plasma proteins that play an important role in the innate immune system against invading pathogens owing to a high affinity for the lipopolysaccharides of Gram-negative bacteria 3,6 . PLUNC proteins are suggested to be host defence molecules because their expression alters in response to inflammation caused by smoking, chemical irritants, and infection 7,8 . CETP and PLTP are both plasma proteins that play an important role in lipoprotein metabolism 9,10 . Recently, the expression of BPIF family of genes has been reported in the brain 11 . We have also reported the expression of BPIF family of genes, such as bpifa1, gm1006 and rya3 in the mouse brain, particularly in the preoptic area 12 . The expression of these genes decreases with age. Because ageing causes oxidative stress and inflammation in the brain 13 , the identified BPIF family of genes might respond to oxidative stress and inflammation similar to the PLUNC protein grou...

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Both full length‐cholesteryl ester transfer protein and exon 9‐deleted cholesteryl ester transfer protein promote triacylglycerol storage in cultured hepatocytes

Liu

Mihna

Izem

et al. 2021

Lipids

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We previously reported that overexpression of full‐length cholesteryl ester transfer protein (FL‐CETP), but not its exon 9‐deleted variant (∆E9‐CETP), in an adipose cell line reduces their triacylglycerol (TAG) content. This provided mechanistic insight into several in vivo studies where FL‐CETP levels are inversely correlated with adiposity. However, increased FL‐CETP is also associated with elevated hepatic lipids, suggesting that the effect of CETP on cellular lipid metabolism may be tissue‐specific. Here, we directly investigated the role of FL‐CETP and ∆E9‐CETP in hepatic lipid metabolism. FL‐ or ∆E9‐CETP was overexpressed in HepG2‐C3A by adenovirus transduction. Overexpression of either FL or ∆E9‐CETP in hepatocytes increased cellular TAG mass by 25% but reduced TAG secretion. This cellular TAG was contained in larger and more numerous lipid droplets. Analysis of TAG synthetic and catabolic pathways showed that this elevated TAG content was due to increased incorporation of fatty acid into TAG (24%), and higher de novo synthesis of fatty acid (50%) and TAG from acetate (40%). siRNA knockdown of CETP had the opposite effect on TAG synthesis and lipogenesis, and decreased cellular TAG. This novel increase in cellular TAG by FL‐CETP overexpression was reproduced in Caco‐2 intestinal epithelial cells. We conclude that, unlike that seen in adipocyte cells, overexpression of either CETP isoform in lipoprotein‐secreting cells promotes the accumulation of TAG. These data suggest that the in vivo correlation between CETP levels and hepatic steatosis can be explained, in part, by a direct effect of CETP on hepatocyte cellular metabolism.

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

Cited by 17 publications

References 58 publications

Defective triglyceride biosynthesis in CETP-deficient SW872 cells

Defective triglyceride biosynthesis in CETP-deficient SW872 cells

Bpifcl modulates kiss2 expression under the influence of 11-ketotestosterone in female zebrafish

Both full length‐cholesteryl ester transfer protein and exon 9‐deleted cholesteryl ester transfer protein promote triacylglycerol storage in cultured hepatocytes

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