Sterol regulatory element-binding proteins induce an entire pathway of cholesterol synthesis.
To evaluate the effects of sterol regulatory element-binding proteins (SREBPs) on the expression of the individual enzymes in the cholesterol synthetic pathway, we examined expression of these genes in the livers from wild-type and transgenic mice overexpressing nuclear SREBP-1a or -2. As estimated by a Northern blot analysis, overexpression of nuclear SREBP-1a or -2 caused marked increases in mRNA levels of the whole battery of cholesterogenic genes. This SREBP activation covers not only rate-limiting enzymes such as HMG CoA synthase and reductase that have been well established as SREBP targets, but also all the enzyme genes in the cholesterol synthetic pathway tested here. The activated genes include mevalonate kinase, mevalonate pyrophosphate decarboxylase, isopentenyl phosphate isomerase, geranylgeranyl pyrophosphate synthase, farnesyl pyrophosphate synthase, squalene synthase, squalene epoxidase, lanosterol synthase, lanosterol demethylase, and 7-dehydro-cholesterol reductase. These results demonstrate that SREBPs activate every step of cholesterol synthetic pathway, contributing to an efficient cholesterol synthesis.
Sakakura
Y
Y
Division of Metabolism and Endocrinology, Department of Internal Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukubashi, Ibaraki 305, Japan.
Shimano
H
H
Sone
H
H
Takahashi
A
A
Inoue
N
N
Toyoshima
H
H
Suzuki
S
S
Yamada
N
N
Inoue
K
K
D000818:Animals; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000096:biosynthesis*; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D011756:Diphosphates / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D051379:Mice; D008822:Mice, Transgenic; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D022762:CCAAT-Enhancer-Binding Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D011756:Diphosphates; C497388:Srebf1 protein, mouse; C497391:Srebf2 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors; D002784:Cholesterol