Peroxisome proliferator-activated receptor-alpha ligands inhibit cardiac lipoprotein lipase activity

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated tr anscription factors that regulate gene expression of lipoprotein lipase (LP L) in liver and adipose tissue. We examined the direct effect of PPAR-alpha ligands on LPL catalytic activity in cultured cardiomyocytes from adult ra t heart. After overnight culture (16 h), 1 muM Wy-14643 and 10 muM BM-17.07 44 decreased total cellular LPL activity to similar to 50% of control with no change in enzyme synthesis or mass; as a consequence, PPAR-alpha activat ion produced a significant decrease in LPL specific activity (mU/ng LPL pro tein). Wy-14643 and BM-17.0744 also reduced heparin-releasable LPL activity and mass in the culture medium. Inhibition of LPL activity by Wy-14643 did not reduce the ability of insulin plus dexamethasone to stimulate cellular and heparin-releasable LPL activities. A similar inhibitory effect on cell ular and heparin-releasable LPL activity was observed when cardiomyocytes w ere cultured with 60 muM linoleic acid. In conclusion, two different PPAR-a lpha ligands (Wy-14643 and BM-17.0744) inhibited cellular LPL activity in c ultured cardiomyocytes by a posttranscriptional and posttranslational mecha nism.