Glycerol and glycerol-3-phosphate: multifaceted metabolites in metabolism, cancer and other diseases

Glycerol and glycerol-3-phosphate are key metabolites at the intersection of carbohydrate, lipid and energy metabolism. Their production and usage are organismal and cell type specific. Glycerol has unique physicochemical properties enabling it to function as an osmolyte, protein structure stabilizer, antimicrobial and antifreeze agent, important to preservation of many biological functions. Glycerol and glycerol-3-phosphate are implicated in many physiological and disease processes relating to energy metabolism, thermoregulation, hydration, skin health, male fertility, aging, and cancer. Glycerol has countless applications in the food, pharmaceutical and cosmetics industries. It is used as a sweetener, preservative, thickening agent, humectant, osmolyte and cryoprotectant. It is widely used in skin and wound care products, laxatives, in cell and tissue preservation and in medicines for numerous conditions. Here, we review the multiple uses and functions of glycerol and glycerol-3-phosphate and associated transporters, enzymes and target genes in health, senescence and disease. We discuss the evidence that glycerol may be present at much higher levels in tissues and cells than in the blood. We bring particular focus to the newly identified glycerol shunt in the direct formation of glycerol independent of lipolysis and as a pathway allowing cells to adapt to various stresses. Relevant to chronic metabolic diseases, cancer and aging, glycerol and glycerol-3-phosphate presents important translational implications and thus warrants much more attention.