Regulating Lipid Storage

Abstract

The accumulation of intracellular lipid stores is an essential process, but excess storage is also associated with metabolic diseases such as insulin resistance. Furthermore, lipid-loaded macrophages, called foam cells, are associated with atherosclerosis. Andersson et al . show that insulin signals through phospholipase D1 (PLD1) and extracellular signal-regulated kinase 2 (ERK2) to stimulate lipid droplet formation in NIH 3T3 cells. Even in the absence of stimuli, overexpression of PLD1 but not PLD2, or ERK2 but not ERK1, promoted the formation of lipid droplets. RNAi technology demonstrated that reduction in PLD1 or ERK2 inhibited lipid droplet formation, and short-interfering RNA (siRNA) against ERK2 prevented the increase in lipid droplets caused by overexpression of PLD1, suggesting that ERK2 is downstream of PLD1. However, the abundance of PLD1 did not alter the abundance of phosphorylated (and presumably active) ERK2. Thus, the exact relationship between PLD1 and ERK2 remains to be determined. The insulin-mediated increase in lipid storage was blocked by siRNA against PLD1 or by the presence of an ERK2 inhibitor (Ste-Mek1 13 ). Analysis of the phosphorylated proteins in cell homogenates exposed to active ERK2 showed that the microtubule motor dynein was phosphorylated. Microtubules have been implicated in fusion of lipid particles that bud from the microsomal membranes, which is the basis for the formation of large lipid storage droplets. Phosphorylated dynein was isolated from lipid droplets, and in vitro the association of dynein with lipid droplets was increased when the cell lysates were exposed to active ERK2. Inhibition of dynein by microinjection of an antibody against dynein intermediate chain prevented lipid droplet formation by inhibiting fusion. Thus, these results provide evidence for an ERK2-specific function in lipid storage. L. Andersson, P. Boström, J. Ericson, M. Rutberg, B. Magnusson, D. Marchesan, M. Ruiz, L. Asp, P. Huang, M. A. Frohman, J. Borén, S.-O. Olofsson, PLD1 and ERK2 regulated cytosolic lipid droplet formation. J. Cell Sci. 119 , 2246-2257 (2006). [Abstract] [Full Text]