108 Regulation of lipoprotein metabolism by thiazolidine-diones occurs through a distinct, but complementary mechanism relative to fibrates

Lefèbvre, Andrée; Peinado-Onsurbe, Júlia; Leitersdorf, Iris; Briggs, Michael R.; Paterniti, James R.; Fruchart, J.C.; Fiévet, Catherine; Auwerx, Johan; Staels, Bart

doi:10.1016/s0021-9150(97)87529-6

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“…In adipose tissue, the increase in FATP, ACS, and LPL (27) production after treatment with thiazolidinediones will enhance the clearance of plasma triglycerides (27,56) and provide the (pre)adipocytes with additional fatty acids, which can further stimulate the transactivation capacity of PPAR or which can be stored under form of triglycerides. In the liver, the enhanced production of FATP and ACS after fibrates together with the increase in ␤ oxidation and the reduced production of apoCIII (57), may contribute to the hypolipidemic action of these compounds.…”

Section: Discussionmentioning

confidence: 99%

Coordinate Regulation of the Expression of the Fatty Acid Transport Protein and Acyl-CoA Synthetase Genes by PPARα and PPARγ Activators

Martin

Schoonjans

Lefebvre

et al. 1997

Journal of Biological Chemistry

484

295

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Intracellular fatty acid (FA) concentrations are in part determined by a regulated import/export system that is controlled by two key proteins, i.e. fatty acid transport protein (FATP) and acyl-CoA synthetase (ACS), which respectively facilitate the transport of FAs across the cell membrane and their esterification to prevent their efflux. The aim of this investigation was to analyze the expression pattern of FATP and ACS and to determine whether their expression was altered by agents that affect FA metabolism through the activation of peroxisome proliferator-activated receptors (PPAR) such as the fibrates and thiazolidinediones. FATP mRNA was ubiquitously expressed, with highest levels being detected in adipose tissue, heart, brain, and testis. Fibrate treatment, which is known to preferentially activate PPAR␣, induced FATP mRNA levels in rat liver and intestine and induced ACS mRNA levels in liver and kidney. The antidiabetic thiazolidinedione BRL 49653, which is a high-affinity ligand for the adipocyte-specific PPAR␥ form, caused a small induction of muscle but a robust induction of adipose tissue FATP mRNA levels. BRL 49653 did not affect liver FATP and had a tendency to decrease heart FATP mRNA levels. ACS mRNA levels in general showed a similar pattern after BRL 49653 as FATP except for the muscle where ACS mRNA was induced. This regulation of FATP and ACS expression by PPAR activators was shown to be at the transcriptional level and could also be reproduced in vitro in cell culture systems. In the hepatocyte cell lines AML-12 or Fa 32, fenofibric acid, but not BRL 49653, induced FATP and ACS mRNA levels, whereas in the 3T3-L1 preadipocyte cell line, the PPAR␥ ligand induced FATP and ACS mRNA levels quicker than fenofibric acid. Inducibility of ACS and FATP mRNA by PPAR␣ or ␥ activators correlated with the tissue-specific distribution of the respective PPARs and was furthermore associated with a concomitant increase in FA uptake. Most interestingly, thiazolidinedione antidiabetic agents seem to favor adipocyte-specific FA uptake relative to muscle, perhaps underlying in part the beneficial effects of these agents on insulin-mediated glucose disposal.

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Section: Discussionmentioning

confidence: 99%