The twists and turns of sphingolipid pathway in glucose regulation

Abstract

Palmitic acid is a saturated fat found in foods that lead to obesity, cardiovascular disease, and Type II diabetes. It is linked to the development of resistance to insulin stimulation in muscle, liver and other organs involved in glucose metabolism, which, in turn, underlines the onset of Type II diabetes. The cellular and molecular mechanisms of this insulin resistance are complex and not completely understood. This article is focused on the role of palmitic acid as a precursor in the synthesis of sphingolipids, a class of lipid molecules that participate in cellular stress response. Recent evidence had indicated that increased dietary supply of palmitate can stimulate the rate of sphingolipid synthesis in "lean" tissues and generate excessive amounts of sphingolipid metabolites that have a negative effect on the insulin signaling cascade. Many experimental results point to the existence of a causative link between sphingolipid synthesis, insulin response, and hyperglycemia. It is not yet clear, however whether ceramides or glycosphingolipids are involved as both have been implicated to be inhibitors of the insulin signaling cascade. Evidence for a coordinated regulation of sphingolipid and tri/diacylglycerol metabolism complicates further the delineation of a single mechanism of sphingolipid effect on glucose homeostasis.

Fig. 1

Schematic representation of the de novo synthesis of sphingolipids.

Fig. 2

Proposed interplay between TAG, glycerophospholipids and sphingolipid metabolism. De novo synthesis of sphingolipids occurs via SPT in the endoplasmic reticulum. A ceramide transfer protein transports ceramide to the Golgi apparatus, where complex sphingolipids, like SM and glycosphingolipids (not shown) are synthesized. Complex sphingolipids are then transferred to the plasma membrane, which contains more then 75% of the total cellular sphingolipids. The synthesis of both TAG and glycerophospholipid from activated fatty acids follows a common pathway to the formation of DAG. DAG can be used either for TAG synthesis, storage, and secretion or for synthesis of the two main glycerophospholipid classes, phosphatidylcholine (PC) or phosphatidylserine (PS). Metabolically, the sphingolipid, glycerophosoholipid and TAG pathways are linked through SM synthase, shown in the middle of the diagram. Exogenous palmitic acid partitions in a competitive fashion between sphingolipid and TAG pools. DAG and ceramide (boxed in the middle) are bioactive metabolites implicated in down-regulation of insulin signaling cascade. As the diagram indicates, they are in the crossroad of mulltiple pathways and their levels are subject to complex regulation.