Involvement of the peroxisome proliferator-activated receptor alpha in regulating long-chain acyl-CoA thioesterases.
Long-chain acyl-CoA thioesterases catalyze the hydrolysis of acyl-CoAs to the corresponding free fatty acid and CoA. We recently cloned four members of a novel multi-gene family of peroxisome proliferator-induced genes encoding cytosolic (CTE-I), mitochondrial (MTE-I), and peroxisomal (PTE-Ia and PTE-Ib) acyl-CoA thioesterases (Hunt et al. 1999. J. Biol. Chem. 274: 34317-34326). As the peroxisome proliferator-activated receptor alpha (PPARalpha) plays a central role in regulating genes involved in lipid metabolism, we examined the involvement of this receptor in regulation of the thioesterases, particularly CTE-I and MTE-I. Northern blot analysis shows that the induction of these thioesterases by clofibrate is mediated through a strictly PPARalpha-dependent mechanism. All four acyl-CoA thioesterases are induced at mRNA level by fasting and using PPARalpha-null mice, it is evident that the increase in CTE-I due to fasting is mainly independent of the PPARalpha in liver and heart. The CTE-I gene responds rapidly to fasting, with induction of mRNA and protein evident after 6 h. This fasting effect is rapidly reversible, with CTE-I mRNA returning almost to control levels after 3 h refeeding, and being further repressed to 20% of control after 9 h refeeding. Although CTE-I mRNA shows a low basal expression in liver, it can be suppressed 90% by feeding a fat-free diet. These data demonstrate that the nutritional regulation of the thioesterases involves the PPARalpha and other signaling pathways responsible for activation and repression. Putative physiological functions for the acyl-CoA thioesterases are discussed.
Hunt
M C
MC
Department of Medical Laboratory Sciences and Technology, Division of Clinical Chemistry, Karolinska Institutet, Huddinge University Hospital, Sweden.
Lindquist
P J
PJ
Peters
J M
JM
Gonzalez
F J
FJ
Diczfalusy
U
U
Alexson
S E
SE
D000818:Animals; D001483:Base Sequence; D002940:Circadian Rhythm; D018076:DNA, Complementary / Q000235:genetics; D004041:Dietary Fats / Q000008:administration & dosage; D005215:Fasting / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D005810:Multigene Family; D009206:Myocardium / Q000378:metabolism; D010170:Palmitoyl-CoA Hydrolase / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D018076:DNA, Complementary; D004041:Dietary Fats; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D010170:Palmitoyl-CoA Hydrolase