Modulation of the hepatic fatty acid pool in peroxisomal 3-ketoacyl-CoA thiolase B-null mice exposed to the selective PPARalpha agonist Wy14,643.
The peroxisomal 3-ketoacyl-CoA thiolase B (Thb) gene was previously identified as a direct target gene of PPARalpha, a nuclear hormone receptor activated by hypolipidemic fibrate drugs. To better understand the role of ThB in hepatic lipid metabolism in mice, Sv129 wild-type and Thb null mice were fed or not the selective PPARalpha agonist Wy14,643 (Wy). Here, it is shown that in contrast to some other mouse models deficient for peroxisomal enzymes, the hepatic PPARalpha signaling cascade in Thb null mice was normal under regular conditions. It is of interest that the hypotriglyceridemic action of Wy was reduced in Thb null mice underlining the conclusion that neither thiolase A nor SCPx/SCP2 thiolase can fully substitute for ThB in vivo. Moreover, a significant increased in the expression of lipogenic genes such as Stearoyl CoA Desaturase-1 (SCD1) was observed in Thb null mice fed Wy. Elevation of Scd1 mRNA and protein levels led to higher SCD1 activity, through a molecular mechanism that is probably SREBP1 independent. In agreement with higher SCD1, enrichment of liver mono-unsaturated fatty acids of the n-7 and n-9 series was found in Thb null mice fed Wy. Overall, we show that the reduced peroxisomal beta-oxidation of fat observed in Thb null mice fed Wy is associated with enhanced hepatic lipogenesis, through the combined elevation of microsomal SCD1 protein and activity. Ultimately, not only the amount but also the quality of the hepatic fatty acid pool is modulated upon the deletion of Thb.
Arnauld
Ségolène
S
Centre de recherche INSERM U866, Laboratoire de Biochimie Métabolique et Nutritionnelle, 6, Boulevard Gabriel, Dijon F-21000, France.
Fidaleo
Marco
M
Clémencet
Marie-Claude
MC
Chevillard
Grégory
G
Athias
Anne
A
Gresti
Joseph
J
Wanders
Ronald J
RJ
Latruffe
Norbert
N
Nicolas-Francès
Valérie
V
Mandard
Stéphane
S
D000101:Acetyl-CoA C-Acetyltransferase / Q000378:metabolism; D000818:Animals; D005227:Fatty Acids / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D047493:PPAR alpha / Q000037:antagonists & inhibitors*; D020675:Peroxisomes / Q000187:drug effects* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects; D013230:Stearoyl-CoA Desaturase / Q000378:metabolism*
D005227:Fatty Acids; D047493:PPAR alpha; D011743:Pyrimidines; D012333:RNA, Messenger; C006253:pirinixic acid; D013230:Stearoyl-CoA Desaturase; D000101:Acetyl-CoA C-Acetyltransferase