Peroxisome proliferator activated receptor α (PPARα) and PPAR gamma coactivator (PGC-1α) induce carnitine palmitoyltransferase IA (CPT-1A) via independent gene elements

Abstract

Long chain fatty acids and pharmacologic ligands for the peroxisome proliferator activated receptor alpha (PPARα) activate expression of genes involved in fatty acid and glucose oxidation including carnitine palmitoyltransferase-1A (CPT-1A) and pyruvate dehydrogenase kinase 4 (PDK4). CPT-1A catalyzes the transfer of long chain fatty acids from acyl-CoA to carnitine for translocation across the mitochondrial membranes and is an initiating step in the mitochondrial oxidation of long chain fatty acids. PDK4 phosphorylates and inhibits the pyruvate dehydrogenase complex (PDC) which catalyzes the conversion of pyruvate to acetyl-CoA in the glucose oxidation pathway. The activity of CPT-1A is modulated both by transcriptional changes as well as by malonyl-CoA inhibition. In the liver, CPT-1A and PDK4 gene expression are induced by starvation, high fat diets and PPARα ligands. Here, we characterized a binding site for PPARα in the second intron of the rat CPT-1A gene. Our studies indicated that WY14643 and long chain fatty acids induce CPT-1A gene expression through this element. In addition, we found that mutation of the PPARα binding site reduced the expression of CPT-1A-luciferase vectors in the liver of fasted rats. We had demonstrated previously that CPT-1A was stimulated by the peroxisome proliferator activated receptor gamma coactivator (PGC-1α) via sequences in the first intron of the rat CPT-1A gene. Surprisingly, PGC-1α did not enhance CPT-1A transcription through the PPARα binding site in the second intron. Following knockdown of PGC-1α with short hairpin RNA, the CPT-1A and PDK4 genes remained responsive to WY14643. Overall, our studies indicated that PPARα and PGC-1α stimulate transcription of the CPT-1A gene through different regions of the CPT-1A gene.

Role of Sirtuin 1 in the Regulation of Hepatic Gene Expression by Thyroid Hormone

“…pdk4 is induced by FoxO1 and ERR␣ (32,49). The cpt1a gene is stimulated by PPAR␣, whereas the pepck is regulated by both hepatic nuclear factor 4 and FoxO1 (50,51). Thus, in addition to TR␤ and PGC-1␣, SIRT1 may target several factors to enhance the T 3 induction in a gene-specific manner.…”

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

“…PPARa transcriptional activity is further enhanced by the coactivator peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1a) (Vega et al 2000, Song et al 2010. As evidence for the central role of PPARa in coordinating the hepatic adaptation to fasting, fasted PPARa null mice are hypoglycemic and fail to become ketotic (Kersten et al 1999, Leone et al 1999.…”

<small>L</small>-Lysine Attenuates Hepatic Steatosis in Senescence-Accelerated Mouse Prone 8 Mice

“…3B). We quantified the mRNA level of the ␤-oxidation related genes PPAR␣ (23,24), CPT-1a (25,26), and ACO (27) in the liver using qRT-PCR. The mRNA expression level of PPAR␣ in the P group tended to be lower than that of the R group (pϭ0.09 vs. P), showing that dietary supplementation with Lys tended to increase PPAR␣ mRNA levels (Fig.…”