Deficiency of PPARalpha disturbs the response of lipogenic flux and of lipogenic and cholesterogenic gene expression to dietary cholesterol in mouse white adipose tissue.
PPARalpha-deficiency in mice fed a high-carbohydrate, low-cholesterol diet was associated with a decreased weight of epididymal adipose tissue and an increased concentration of adipose tissue cholesterol. Consumption of a high (2% w/w) cholesterol diet resulted in a further increase in the concentration of cholesterol and a further decrease in epididymal fat pad weight in PPARalpha-null mice, but had no effect in the wild-type. These reductions in fat pad weight were associated with an increase in hepatic triacylglycerol content, indicating that both PPARalpha-deficiency and cholesterol altered the distribution of triacylglycerol in the body. Adipose tissue de novo lipogenesis was increased in PPARalpha-null mice and was further enhanced when they were fed a cholesterol-rich diet; no such effect was observed in the wild-type mice. The increased lipogenesis in the chow-fed PPARalpha-null mice was accompanied paradoxically by lower mRNA expression of SREBP-1c and its target genes, acetyl-CoA carboxylase and fatty acid synthase. Consumption of a high-cholesterol diet increased the mRNA expression of these genes in the PPARalpha-deficient mice but not in the wild-type. De novo cholesterol synthesis was not detectable in the adipose tissue of either genotype despite a relatively high expression of the mRNA's encoding SREBP-2 and 3-hydroxy-3-methylglutaryl Coenzyme A reductase. The mRNA expression of these genes and of the LDL-receptor in adipose tissue of the PPARalpha-deficient mice was lower than that of the wild-type and was not downregulated by cholesterol feeding. The results suggest that PPARalpha plays a role in adipose tissue cholesterol and triacylglycerol homeostasis and prevents cholesterol-mediated changes in de novo lipogenesis.
Islam
K K
KK
Metabolic Research Laboratory, OCDEM, Churchill Hospital, Oxford OX3 7LJ, UK.
Knight
B L
BL
Frayn
K N
KN
Patel
D D
DD
Gibbons
G F
GF
D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis; D002791:Cholesterol, Dietary / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004822:Epididymis / Q000033:anatomy & histology / Q000378:metabolism; D005227:Fatty Acids / Q000096:biosynthesis / Q000378:metabolism; D015870:Gene Expression; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008099:Liver / Q000033:anatomy & histology / Q000378:metabolism*; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size; D057093:Orphan Nuclear Receptors; D047493:PPAR alpha / Q000172:deficiency* / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors / Q000378:metabolism
D002791:Cholesterol, Dietary; D004268:DNA-Binding Proteins; D005227:Fatty Acids; D008055:Lipids; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047493:PPAR alpha; D018160:Receptors, Cytoplasmic and Nuclear; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors; D002784:Cholesterol