Abstract
We previously reported that reducing the expression of cholesteryl ester transfer protein (CETP) disrupts cholesterol homeostasis in SW872 cells and causes an ∼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-deficient cells, nor was there evidence of endoplasmic reticulum (ER) stress. In short-term studies, the total flux of oleate through the TG biosynthetic pathway was not altered in CETP-deficient 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 inefficiently 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-deficient cells arises from the reduced conversion of DG to TG in the ER and/or on the lipid droplet surface, and enhanced TG degradation in the ER due to its ineffective transport from this organelle.
Highlights
We previously reported that reducing the expression of cholesteryl ester transfer protein (CETP) disrupts cholesterol homeostasis in SW872 cells and causes an ف50% reduction in TG
We previously reported that CETP-deficient cells accumulate about half as much TG as vector-transfected control cells, and that lipid droplets in these cells are smaller and fewer in number [10]
While PLIN1 levels were similar in oleatetreated control and CETP-deficient cells, PLIN2 levels were markedly lower and PLIN3 levels were elevated 2-fold in CETP-deficient cells compared with oleate-treated control cells (Fig. 1B)
Summary
We previously reported that reducing the expression of cholesteryl ester transfer protein (CETP) disrupts cholesterol homeostasis in SW872 cells and causes an ف50% reduction in TG. DG, shown to be a novel CETP substrate, was inefficiently 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-deficient cells arises from the reduced conversion of DG to TG in the ER and/or on the lipid droplet surface, and enhanced TG degradation in the ER due to its ineffective transport from this organelle.—Greene, D. 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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