On the mechanism for PPAR agonists to enhance ABCA1 gene expression

Abstract

Expression of ATP binding cassette transporter A1 (ABCA1), a major regulator of high density lipoprotein (HDL) biogenesis, is known to be up-regulated by the transcription factor liver X receptor (LXR) α, and expression is further enhanced by activation of the peroxisome proliferator activated receptors (PPARs). We investigated this complex regulatory network using specific PPAR agonists: four fibrates (fenofibrate, bezafibrate, gemfibrozil and LY518674), a PPAR δ agonist (GW501516) and a PPAR γ agonist (pioglitazone). All of these compounds increased the expression of LXRs, PPARs and ABCA1 mRNAs, and associated apoA-I-mediated lipid release in THP-1 macrophage, WI38 fibroblast and mouse fibroblast. When mouse fibroblasts lacking expression of PPAR α were examined, the effects of fenofibrate and LY518674 were markedly diminished while induction by other ligands were retained. The PPAR α promoter was activated by all of these compounds in an LXR α-dependent manner, and partially in a PPAR α-dependent manner, in mouse fibroblast. The LXR responsive element (LXRE)-luciferase activity was enhanced by all the compounds in an LXR α-dependent manner in mouse fibroblast. This activation was exclusively PPAR α-dependent by fenofibrate and LY518674, but nonexclusively by the others. We conclude that PPARs and LXRs are involved in the regulation of ABCA1 expression and HDL biogenesis in a cooperative signal transduction pathway.

High Density Lipoprotein Turnover is Dependent on Peroxisome Proliferator-Activated Receptor α in Mice

“…The expression of ABCA1, LXR and PPAR mRNA decreased in the liver of PPAR -null mice, consistent with earlier findings in these mice 19) . PPAR mRNA also tended to decrease but failed to reach statistical significance.…”

“…Expressions of ABCA1, LXR and PPAR were reduced in the liver of PPAR -null mice, consistent with our previous findings in fibroblasts derived from PPAR -null mice 19) . These genes are all involved in HDL biogenesis so that production of HDL is likely reduced in these animals.…”

“…The expression of PPAR was decreased in the liver of PPAR -null mice. Since PPAR and LXR activate each other 19) , it is likely that other PPAR subtypes also form such circuits and the lack of PPAR would lead to the decreased PPAR expression. However, PPAR expression did not significantly decrease under PPAR deficiency in this particular experiment.…”

“…PCR was carried out for cDNA using primers Western Blotting ABCA1 and SR-BI proteins were analyzed in the liver and adrenal glands, respectively, using a specific antibody raised against a C-terminal peptide of ABCA1 19) and anti-AR-BI antibody purchased from Novus Biochemicals (NB 400-131). Anti--actin antibody (A5441) was used to detect a loading control.…”

“…PPAR is predominantly involved in energy homeostasis via the regulation of fatty acid metabolism, but it is also associated with sterol homeostasis through the liver X receptor (LXR) system, as demonstrated by its pharmacological stimulation by fibrates. High density lipoprotein (HDL) metabolism is especially influenced by activation of PPAR , directly and indirectly, to reduce plasma triglyceride to increase HDL-cholesterol in the presence of plasma cholesterol ester transfer protein 14) , and by up-regulating the genes to raise HDL such as apolipoprotein A-I (apoA-I) 15) and ATP binding cassette transporter A1 (ABCA1) [16][17][18] , using a complicated network of nuclear receptors, including LXRs 19) . There are many inconsistencies among the reports on lipid metabolism and energy metabolism in PPAR -null mice.…”