The non-energetic functions of triacylglycerol (triglycerides) in human cells: role in cell membrane synthesis and cell signaling.

Phospholipids, which are molecules with both structural and potential signaling functions, and triacylglycerols (TAG, also called triglycerides), which form the main energy store within cells, are metabolically interconnected by the exchange of common lipid intermediates. An emerging body of data indicates that in mammalian cells in which TAG is not stored for energetic purposes, TAG metabolism plays a critical role in functions such as signaling and membrane lipid synthesis. Alterations of TAG in nonadipose cells such as pancreatic β-cells and cardiac cells is thought to be a marker of or to be responsible for the onset of diseases such as type 2 diabetes mellitus and heart dysfunction. Nevertheless, the regulation of TAG synthesis and recycling in nonadipose cells is still not well understood.

It has been observed that lipid intermediates of TAG and phospholipid metabolism, such as diacylglycerol (DAG) and fatty acids, are exchanged in a recycling pathway that could be potentially relevant for membrane synthesis and lipid signal transduction. DAG is a versatile lipid molecule that exhibits a dual role in cell biology serving both as substrate for cell membrane (phospholipids) and energy storage (TAG) lipids, as well as second messengers for signal transduction events related to cell proliferation, differentiation and death (Figure 1). The content and metabolic fate of DAG must be tightly controlled since it has been observed that chronically high levels of the DAG play a critical role in the progression of some types of cancer, in part due to the misfunction of DAG sensitive-signaling proteins like protein kinase C (PKCs), RasGRP, etc. Our laboratory has shown that modulating the channeling of DAG into the triacylglycerol stores by overexpressing diacylglycerol acyltransferase (DGAT), the last committed enzyme in TAG synthesis, can alter cell growth and cancer transformation. Nevertheless, the molecular mechanisms by which the preferential channeling of DAG into TAG attenuates the biological and biochemical phenotype of neoplastic cells are unknown and are currently under investigation in our laboratory.

Figure 1

Stearoyl CoA Desaturase (SCD), a global regulator of lipid synthesis and a novel target for cancer therapy

Cancer is a leading cause of death worldwide, with lung, prostate and breast cancer at the top of the list of the most frequent and lethal cancer types. Unfortunately, conventional treatments have only a modest global impact on mortality hence, in the search of more successful therapies, attention has been centered on new molecular targets such as lipid metabolism. To sustain their unrestricted capacity for proliferation, cancer cells must constantly produce essential structural components like plasma membrane and inner membranes, which are mostly composed of a special variety of lipids, the phospholipids. Phospholipids are made of different species of fatty acids, mainly consisting of the more rigid saturated (SFA) and the more fluid monounsaturated (MUFA) fatty acids. Therefore, the relative abundance of both MUFA and SFA will determine the structure and functions of cellular membranes and also crucial energy storage lipids, which will ultimately regulate the length and characteristics of cell life. The abundance of these fatty acid species produced within the cell is regulated by the Stearoyl CoA Desaturase (SCD), the enzyme that converts SFA into MUFA (Figure 2). We and other investigators have reported that, unlike normal cells, SCD is constitutively activated in a variety of human cancer cells. Therefore, our long term objective is to understand the regulation of SCD during cancer development and progression and ultimately develop novel therapeutic approaches to eradicate tumors based on the suppression of SCD. We recently discovered that SCD is a global regulator of lipid metabolism in human cancer cells and that the stable ablation of SCD gene expression dramatically reduces or suppresses cancer cell growth, invasiveness and tumor formation in mice. Using infecting viral particles or oligonucleotides carrying the antisense SCD sequence we are able to manipulate the levels of SCD expression and activity in cultured lung and breast cancer cells and in mice tumor models in order to investigate 1) the consequences on in vitro cancer cell growth, adhesion, migration and angiogenesis; and 2) the ability of tumors to growth, form new blood vessels, invade and colonize distant organs.

Selected recent publications

Igal, R. A., Caviglia, J. M., I. de Gómez Dumm, N. T., and Coleman, R. A.  Diacylglycerol generated in CHO cell plasma membrane by phospholipase C is channeled towards triacylglycerol synthesis (2001). J. Lipid Res. 42:88-95.

Igal, R. A., Wang, S, Gonzalez-Baró, M. R., Coleman, R.A. Mitochondrial glycerol phosphate acyltransferase directs the incorporation of exogenous fatty acids into triacylglycerol. 2001. J. Biol. Chem. 276:42205-12

C. Bagnato, R. A. Igal.  Overexpression of diacylglycerol acyltransferase-1 reduces phospholipid synthesis, proliferation and invasiveness in SV40-transformed human lung fibroblasts. (2003) J. Biol. Chem. 278:52203-11

Caviglia, J. M., Gómez Dumm. I. N. T., Coleman, R. A., Igal, R. A. Phosphatidylcholine deficiency up-regulates enzymes of triacylglycerol metabolism in CHO cells (2004) J. Lipid Res. 45:1500-09

Scaglia, N. , Caviglia, J. M., Igal, R. A. High stearoyl-CoA desaturase activity and protein levels in SV40-transformed human lung fibroblasts. (2005) Biochim. Biophys. Acta. 1687:141-51.

Scaglia, N., Igal, R. A. Stearoyl-CoA desaturase controls proliferation, anchorage-independent growth and programmed cell death in human transformed cells. (2005)  J. Biol. Chem. 280:25339-49