Regulation of the metabolism of apolipoprotein M and sphingosine 1-phosphate by hepatic PPARγ activity

Apolipoprotein M (apoM) is a carrier and a modulator of sphingosine 1-phosphate (S1P), an important multifunctional bioactive lipid. Since peroxisome proliferator-activated receptor gamma (PPAR gamma) is reportedly associated with the function and metabolism of S1P, we investigated the modulation of apoM/S1P homeostasis by PPAR gamma. First, we investigated the modulation of apoM and S1P homeostasis by the overexpression or knockdown of PPAR gamma in HepG2 cells and found that both the overexpression and the knockdown of PPAR gamma decreased apoM expression and S1P synthesis. When we activated or suppressed the PPAR gamma more mildly with pioglitazone or GW9662, we found that pioglitazone suppressed apoM expression and S1P synthesis, while GW9662 increased them. Next, we overexpressed PPAR gamma in mouse liver through adenoviral gene transfer and observed that both the plasma and hepatic apoM levels and the plasma S1P levels decreased, while the hepatic S1P levels increased, in the presence of enhanced sphingosine kinase activity. Treatment with pioglitazone decreased both the plasma and hepatic apoM and S1P levels only in diet-induced obese mice. Moreover, the overexpression of apoM increased, while the knockdown of apoM suppressed PPAR. activities in HepG2 cells. These results suggested that PPAR gamma regulates the S1P levels by modulating apoM in a bell-shaped manner, with the greatest levels of apoM/S1P observed when PPAR gamma was mildly expressed and that hepatic apoM/PPAR. axis might maintain the homeostasis of S1P metabolism.