Vitamin A regulates Akt signaling through the phospholipid fatty acid composition

Abstract

Protein kinases, including the serine/threonine kinase Akt, mediate manifold bioactivities of vitamin A, although the mechanisms behind the sustained kinase activation are diffuse. To investigate the role of cellular lipids as targetable factors in Akt signaling, we combined mass spectrometry-based lipidomics with immunologic detection of Akt (Ser473) phosphorylation. A screening campaign revealed retinol (vitamin A alcohol) and all- retinoic acid (vitamin A acid) (RA) as hits that time-dependently (≥24 h) deplete phosphatidylcholine-bound polyunsaturated fatty acids (PUFA-PCs) from NIH-3T3 mouse fibroblasts while inducing Akt activation (EC ≈ 0.1-1 µM). Other mitogenic and stress-regulated kinases were hardly affected. Organized in a coregulated phospholipid subcluster, PUFA-PCs compensated for the RA-induced loss of cellular PUFA-PCs and diminished Akt activation when supplemented. The counter-regulation of phospholipids and Akt by RA was mimicked by knockdown of lysophosphatidylcholine acyltransferase-3 or the selective retinoid X receptor (RXR) agonist bexarotene and prevented by the selective RXR antagonist Hx531. Treatment of mice with retinol decreased the tissue ratio of PUFA-PC and enhanced basal Akt activation preferentially in brain, which was attributed to astrocytes in dissociated cortical cultures. Together, our findings show that RA regulates the long-term activation of Akt by changes in the phospholipid composition.-Pein, H., Koeberle, S. C., Voelkel, M., Schneider, F., Rossi, A., Thürmer, M., Loeser, K., Sautebin, L., Morrison, H., Werz, O., Koeberle, A. Vitamin A regulates Akt signaling through the phospholipid fatty acid composition.

Lysophospholipid acylation modulates plasma membrane lipid organization and insulin sensitivity in skeletal muscle

“…Of the thirteen lyso-PL acyltransferase enzymes (20), LPCAT3 has the highest affinity for 16:0 and 18:0 lyso-PC, consistent with the specificity of reduced lyso-PC/PC (21,22). Silencing of LPCAT3 in fibroblasts has been shown to increase Akt phosphorylation (23), while incubation of the same cells with 16:0/20:4 PC decreased Akt phosphorylation due to plasma-membrane specific effects (24). Mice with a liver-specific deletion of LPCAT3 exhibit enhanced ordering of membranes (25).…”

Z-Ligustilide Combined with Cisplatin Reduces PLPP1-Mediated Phospholipid Synthesis to Impair Cisplatin Resistance in Lung Cancer

“…The relative levels of total PC, PE, PI, PG, PS and TG are shown in Figure 6A. Various components of phospholipids are involved in the activation of AKT [33][34][35]. The Western blot experiment confirmed that Z-ligustilide+cisplatin decreased the level of phospho-AKT (p-AKT); however, PLPP1 silence reversed the expression of p-AKT in A549/DDP and H460/DDP cells (Figure 6B).…”

Z-Ligustilide Combined with Cisplatin Reduces PLPP1-Mediated Phospholipid Synthesis to Impair Cisplatin Resistance in Lung Cancer

“…Relative levels of total PC, PE, PI, PG, PS and TG are shown in Figure 6A. Various components of phospholipids, such as PS, PI, and PC, are involved in the activation of AKT [20][21][22] which plays important roles in cell cycle progression, cell apoptosis and resistance [23]. The western blot experiment confirmed that Z-ligustilide+cisplatin decreased the level of p-AKT, however, PLPP1 silence reversed the expression of p-AKT in A549/DDP and H460/DDP cells (Figure 6B).…”