Farnesyl pyrophosphate regulates adipocyte functions as an endogenous PPARγ agonist

Abstract

The cholesterol biosynthetic pathway produces not only sterols but also non-sterol mevalonate metabolites involved in isoprenoid synthesis. Mevalonate metabolites affect transcriptional and post-transcriptional events that in turn affect various biological processes including energy metabolism. In the present study, we examine whether mevalonate metabolites activate PPARγ (peroxisome-proliferator-activated receptor γ), a ligand-dependent transcription factor playing a central role in adipocyte differentiation. In the luciferase reporter assay using both GAL4 chimaera and full-length PPARγ systems, a mevalonate metabolite, FPP (farnesyl pyrophosphate), which is the precursor of almost all isoprenoids and is positioned at branch points leading to the synthesis of other longer-chain isoprenoids, activated PPARγ in a dose-dependent manner. FPP induced the in vitro binding of a co-activator, SRC-1 (steroid receptor co-activator-1), to GST (glutathione transferase)–PPARγ. Direct binding of FPP to PPARγ was also indicated by docking simulation studies. Moreover, the addition of FPP up-regulated the mRNA expression levels of PPARγ target genes during adipocyte differentiation induction. In the presence of lovastatin, an HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase inhibitor, both intracellular FPP levels and PPARγ-target gene expressions were decreased. In contrast, the increase in intracellular FPP level after the addition of zaragozic acid, a squalene synthase inhibitor, induced PPARγ-target gene expression. The addition of FPP and zaragozic acid promotes lipid accumulation during adipocyte differentiation. These findings indicated that FPP might function as an endogenous PPARγ agonist and regulate gene expression in adipocytes.

Insulin Sensitization by a Novel Partial Peroxisome Proliferator-Activated Receptor γ Agonist With Protein Tyrosine Phosphatase 1B Inhibitory Activity in Experimental Osteoporotic Rats

“…In rat BMSCs, rosiglitazone markedly increased GPDH activity, an adipocyte marker enzyme, and reduced ALP activity, an osteoblast marker enzyme; however, the effects of KY201 at higher concentrations were significantly weaker than those of rosiglitazone. The increasing effects of KY201 on the expression of PPARg2, C/EBPa, GPDH, lipoprotein lipase, adipocyte protein 2, and adiponectin, all bio marker genes of adipocytes (29,32), were also weaker than those of rosiglitazone in rat BMSCs cells. These findings demonstrate that KY201 partially activates PPARg, unlike rosiglitazone, a full PPARg agonist, resulting in fewer PPARgmediated adverse effects.…”

The Role of Acetoacetyl-CoA Synthetase, a Ketone Body-Utilizing Enzyme, in 3T3-L1 Adipocyte Differentiation

“…18,19) Moreover, farnesyl pyrophosphate, which is the precursor of almost all isoprenoids activates PPARγ, and promotes lipid accumulation during adipocyte differentiation. 20) These results suggest that the cholesterol biosynthetic pathway has an important role in adipocyte differentiation. As AACS expression is up-regulated by cholesterol depletion and ketone bodies are incorporated into cholesterol synthesis, 5,7) ketone body utilization by AACS may play an important role in cholesterol synthesis.…”

Metabolomics reveal 1-palmitoyl lysophosphatidylcholine production by peroxisome proliferator-activated receptor α

“…The 3T3-L1 cells were cultured, maintained, and differentiated using a previously described method ( 24 ). Briefl y, 3T3-L1 murine preadipocytes were cultured in a growth medium, DMEM supplemented with 10% (v/v) fetal bovine serum, 100 U/ml penicillin, and 100 µg/ml streptomycin at 37°C in 5% CO 2 .…”