Lipid metabolism and lipophagy in cancer

Abstract

The tumor microenvironment can be hypoxic, acidic, and deficient in nutrients, thus causing the metabolism of tumor cells as well as the neighboring stromal cells to be remodelled to facilitate tumor survival, proliferation, and metastasis. Abnormal tumor lipid metabolism is a fairly new field, which has received attention in the past few years. Cross-talk between tumor cells and tumor-associated stromal cells modulates the high metabolic needs of the tumor. Fatty acid turnover is high in tumor cells to meet the energy as well as synthetic requirements of the growing tumor. Lipolysis of lipids stored in lipid droplets was earlier considered to be solely carried out by cytosolic lipases. However recent studies demonstrate that lipophagy (autophagic degradation of lipids by acidic lipases) serves as an alternate pathway for the degradation of lipid droplets. Involvement of lipophagy in lipid turnover makes it a crucial player in tumorigenesis and metastasis. In this review we discuss the metabolic reprogramming of tumor cells with special focus on lipid metabolism. We also address the lipid turnover machinery in the tumor cell, especially the lipophagic pathway. Finally, we integrate the current understanding of lipophagy with tumor lipid metabolism.

Keywords: Lipid droplets; Lipid metabolism; Lipophagy; Tumor; Tumor microenvironment.

Figure 1

A simplified schematic representation of lipid metabolism in tumor cells. Tumor cells show altered lipid metabolic networks involving catabolism (fatty acid oxidation (FAO)), biosynthesis pathways (de novo lipogenesis) and storage as lipid droplets (LDs). Cancer cells show increased fatty acid (FA) uptake by fatty acid translocase (FAT), CD36, which then undergo β-oxidation in the mitochondrial matrix. Acetyl CoA, the end product of FAO pathway, can then either enter TCA cycle or may be transported to the cytosol in the form of citrate for fatty acid synthesis. Excess acyl CoA can undergo esterification with cholesterol or diacylglycerol (DAG) to form cholesterol ester (CE) or triacylglycerol (TG) and is stored in the form of lipid droplets.

Figure 2

Schematic representation of Lipolysis: Lipid droplet surface proteins PLIN2 and PLIN3 are degraded via chaperone mediated autophagy (CMA). Consequently the LD surface is exposed for the action of neutral cytosolic lipases and lipophagic machinery. A double membrane engulfs a part of or whole LD, thus forming autophagosome which fuses with lysosome to form autolysosome. Lysosomal acid lipases act on the lipids to form free fatty acids. Cytosolic lipases directly act on LD surface to degrade lipids to fatty acids. Subsequently, β-oxidation of fatty acids takes place in mitochondria to generate energy and metabolic intermediates.