Cellular fatty acid metabolism and cancer

The reorganization of metabolic pathways in cancer facilitates the flux of carbon and reducing equivalents into anabolic pathways at the expense of oxidative phosphorylation. This provides rapidly dividing cells with the necessary precursors for membrane, protein and nucleic acid synthesis. A fundamental metabolic perturbation in cancer is the enhanced synthesis of fatty acids by channeling glucose and/or glutamine into cytosolic acetyl-CoA and upregulation of key biosynthetic genes. This lipogenic phenotype also extends to the production of complex lipids involved in membrane synthesis and lipid-based signaling. Cancer cells display sensitivity to ablation of fatty acid synthesis possibly as a result of diminished capacity to synthesize complex lipids involved in signaling or growth pathways. Evidence has accrued that phosphatidylcholine, the major phospholipid component of eukaryotic membranes, as well as choline metabolites derived from its synthesis and catabolism, contribute to both proliferative growth and programmed cell death. This review will detail our current understanding of how coordinated changes in substrate availability, gene expression and enzyme activity lead to altered phosphatidylcholine synthesis in cancer, and how these changes contribute directly or indirectly to malignant growth. Conversely, apoptosis targets key steps in phosphatidylcholine synthesis and degradation that are linked to disruption of cell cycle regulation, reinforcing the central role that phosphatidylcholine and its metabolites in determining cell fate.

The role of phosphatidylcholine and choline metabolites to cell proliferation and survival.

Triacylglycerol (TAG) is the primary unit of energy storage in eukaryotic cells. TAG comprises more than 90% of the content of white adipocytes, and TAG synthesis is essential in enterocytes for the absorption of dietary lipids, in hepatocytes for the synthesis and transport of VLDL, and in mammary epithelial cells for the production of milk. TAG is critical for the formation of the water barrier of skin, it acts as a mechanical cushion within joints and around internal organs, and it also serves an important role in insulation. In virtually every type of cell, stored TAG sequesters essential fatty acids (FAs) and precursors of eicosanoids, as well as the DAG precursor of phospholipids. Storage of FAs in TAG protects cells from the potential detergent-like properties of FAs or their acyl-CoA derivatives which may injure cellular membranes. In addition, recent studies suggest that cellular stores of TAG in lipid droplets release FAs that are channeled selectively to β-oxidation and that act as signals to influence the transcriptional control of gene expression. Additional studies suggest that the process of synthesizing or degrading TAG produces lipid intermediates like lysophosphatidic acid (LPA), phosphatidic acid (PA), and diacylglycerol (DAG) that may serve as activators or inhibitors of signaling pathways controlled by peroxisome proliferator-activated receptor-γ (PPARγ), the mammalian target of rapamycin (mTOR), or protein kinase C (PKC) isoforms. These signaling pathways may link excess intracellular TAG storage with insulin resistance.

It is the goal of this review to provide an overview of TAG metabolism as a dynamic process that allows its lipid participants to play numerous inter-related roles within cells. Thus, we will focus on both the synthesis and degradation of TAG, the enzymes involved and their regulation, and the overall physiological regulation of these dynamic processes. In addition to the lipolytic enzymes, this review will also highlight co-regulatory proteins that affect the activity of specific lipases.

We have chosen to focus primarily on information reported during the past 10 years and recommend to readers several excellent reviews that present more detailed information from older studies: for the synthetic pathway as a whole,1 for GPAT,2 for GPAT, AGPAT and PAP,3–4 for DGAT,5 for the lipolytic pathway and ATGL,6 for HSL,7 and for MGL.8

Mammalian triacylglycerol metabolism: synthesis, lipolysis, and signaling

Effect of ethanol on lipid metabolism

This review describes recent advances in our knowledge of the regulatory interactions influencing the expression of peroxisome proliferator-activated receptor (PPAR)-regulated genes. We address recent advances highlighting the role of PPARgamma (PPARG) coactivator-1 (PGC-1) and lipin-1 in co-ordinating the expression of genes controlling nutrient handling. We evaluate the possibility that SIRT1 lies at the heart of a regulatory loop involving PPARalpha, PGC-1alpha (PPARA, PPARGC1A as given in the HUGO Database), and lipin-1 (LPIN1 as listed in the HUGO Database) that ultimately controls the metabolic response to varying nutrient and physiological signals via a common mechanism mediated by post-translation modifications (deacetylation) of both PPARalpha and PGC-1s. Finally, we comment on the potential of pharmaceutical manipulation of these targets as well as the possible problems associated with this strategy.

/pdf/ppar-control-it-s-sirtainly-as-easy-as-pgc-1mgv2i6w2h.pdf

PPAR control: it's SIRTainly as easy as PGC

Sterol-mediated regulation of human lipin 1 gene expression in hepatoblastoma cells.

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Sterol-mediated regulation of human lipin 1 gene expression in hepatoblastoma cells.