PPARalpha and PPARgamma activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene.

Abstract

Increased activity of lipoprotein lipase (LPL) may explain the hypotriglyceridemic effects of fibrates, thiazolidinediones and fatty acids, which are known activators (and/or ligands) of the various peroxisome proliferator‐activated receptors (PPARs). Treatment with compounds which activate preferentially PPARalpha, such as fenofibrate, induced LPL expression exclusively in rat liver. In contrast, the antidiabetic thiazolidinedione BRL 49653, a high affinity ligand for PPARgamma, had no effect on liver, but induced LPL expression in rat adipose tissue. In the hepatocyte cell line AML‐12, fenofibric acid, but not BRL 49653, induced LPL mRNA, whereas in 3T3‐L1 preadipocytes, the PPARgamma ligand induced LPL mRNA levels much quicker and to a higher extent than fenofibric acid. In both the in vivo and in vitro studies, inducibility by either PPARalpha or gamma activators, correlated with the tissue distribution of the respective PPARs: an adipocyte‐restricted expression of PPARgamma, whereas PPARalpha was expressed predominantly in liver. A sequence element was identified in the human LPL promoter that mediates the functional responsiveness to fibrates and thiazolidinediones. Methylation interference and gel retardation assays demonstrated that a PPARalpha or gamma and the 9‐cis retinoic acid receptor (RXR) heterodimers bind to this sequence −169 TGCCCTTTCCCCC −157. These data provide evidence that transcriptional activation of the LPL gene by fibrates and thiazolidinediones is mediated by PPAR‐RXR heterodimers and contributes significantly to their hypotriglyceridemic effects in vivo. Whereas thiazolidinediones predominantly affect adipocyte LPL production through activation of PPARgamma, fibrates exert their effects mainly in the liver via activation of PPARalpha.

PPARγ insufficiency promotes follicular thyroid carcinogenesis via activation of the nuclear factor-κB signaling pathway

“…Figure 1c shows the loading controls using a-tubulin for the Western blot shown in Figure 1b. To be certain that the reduced expression of PPARg protein in TRb PV/PV mice led to the repression of the PPARg activity, we evaluated the mRNA expression of its direct downstream target gene, the lipoprotein lipase (LpL) (Schoonjans et al, 1996;Goldberg and Merkel, 2001). …”

Direct demonstration of lipid sequestration as a mechanism by which rosiglitazone prevents fatty-acid-induced insulin resistance in the rat: comparison with metformin

“…The intralipid/heparin technique is commonly used to study fatty acid clearance, but in vivo study of the fate of triglycerides derived from lipoprotein particles requires a different technique now being developed [33]. Since rosiglitazone can increase LPL expression [34], it is possible that rosiglitazone increased hydrolysis of triglyceride, but the lower plasma fatty acid levels argue against this. Another possibility is that TZDs inhibited Apo C-III expression [35], which could perhaps lead to enhanced removal of triglyceride-rich particles without lipolysis [36].…”

Thyroid hormone action in metabolic regulation

“…These genes are key regulators of glucose and lipid metabolism. TR has been shown to regulate the transcription of these genes either through TRE or via response elements identified as LXRE or PPRE (Schoonjans et al, 1996;Jansen et al, 2000;Yoshikawa et al, 2001;Araki et al, 2005;Hashimoto et al, 2009;Gauthier et al, 2010). However, most studies were carried out in vitro.…”