Coadministration of a Liver X Receptor Agonist and a Peroxisome Proliferator Activator Receptor-α Agonist in Mice: Effects of Nuclear Receptor Interplay on High-Density Lipoprotein and Triglyceride Metabolism in Vivo

Abstract

Liver X receptors (LXRs) are master transcription factors regulating cholesterol and fatty acid metabolism. Treatment of C57B6 mice with a specific synthetic LXR agonist, N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1(trifluoromethyl)-ethyl]phenyl]-benzenesulfonamide (T0901317), resulted in elevated high-density lipoprotein (HDL) cholesterol as well as plasma and liver triglycerides. Peroxisome proliferator-activated receptor-alpha (PPARalpha) agonists are known to induce peroxisomal fatty acid beta-oxidation and also mediate HDL cholesterol metabolism. We have explored the hypothesis that simultaneous activation of PPARalpha and LXR may lead to additive effects on HDL cholesterol elevation as well as attenuation of triglyceride accumulation. Coadministration of T0901317 and the specific PPARalpha agonist [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (Wy14643)] in mice led to synergistic elevation of HDL cholesterol that was primarily associated with enlarged HDL particles enriched with apoE and apoAI. Liver phospholipid transfer protein (PLTP) mRNA and plasma PLTP activity were additively elevated, suggesting a role of PLTP in the observed HDL cholesterol elevation. Moderate increases in plasma triglyceride levels induced by LXR activation was reduced, whereas the accumulation of triglyceride in the liver was not altered upon coadministration of the PPARalpha agonist. Peroxisomal fatty acid beta-oxidation in the liver was dramatically elevated upon PPARalpha activation as expected. Interestingly, activation of LXRs via T0901317 also led to a significant increase in peroxisomal fatty acid beta-oxidation. Sterol regulatory element binding protein 1c expression was dramatically up-regulated by the LXR agonist but was not changed with PPARalpha agonist treatment. Liver lipoprotein lipase expression was additively increased upon LXR agonist and PPARalpha agonist coadministration. Our studies mark the first exploration of nuclear receptor interplay on lipid homeostasis in vivo.

Liver X receptors as integrators of metabolic and inflammatory signaling

“…36). An attempt to limit increases of hepatic and plasma triglycerides in response to LXR-agonist treatment by increasing hepatic fatty acid oxidation with a PPARα ligand was unsuccessful (37). Although the PPARα ligand strongly increased hepatic fatty acid oxidation, it was unable to counter the hepatic triglyceride accumulation in response to the LXR agonist.…”

Emerging Therapies Targeting High-Density Lipoprotein Metabolism and Reverse Cholesterol Transport

“…Coadministration of an LXR agonist and a PPAR-␣ agonist in mice resulted in a synergistic elevation in HDL-C levels. 70 Additionally, administration of a potent synthetic PPAR-␣ agonist to mice reduced atherosclerosis and inhibited foam cell formation in an ABCA1-independent but LXR-dependent manner. 71 However, no direct data exist yet that PPAR-␣ agonists directly promote RCT in vivo.…”

Novel Peroxisome Proliferator-Activated Receptor α Agonists Lower Low-Density Lipoprotein and Triglycerides, Raise High-Density Lipoprotein, and Synergistically Increase Cholesterol Excretion with a Liver X Receptor Agonist

“…The addition of a PPAR␣ agonist also mitigates some of the undesirable effects of LXR agonists, e.g., hypertriglyceridemia ( Fig. 6C), by possibly superinducing LPL, as has been demonstrated recently (Beyer et al, 2004). It is notable that BMS-711939 not only completely blocked the LXR agonist-induced triglyceride elevation, it reduced triglyceride levels 80% below the baseline.…”