Sterol regulatory element binding protein 1a regulates hepatic fatty acid partitioning by activating acetyl coenzyme A carboxylase 2.
We generated a line of mice in which sterol regulatory element binding protein 1a (SREBP-1a) was specifically inactivated by insertional mutagenesis. Homozygous mutant mice were completely viable despite expressing SREBP-1a mRNA below 5% of normal, and there were minimal effects on expression of either SREBP-1c or -2. Microarray expression studies in liver, where SREBP-1a mRNA is 1/10 the level of the highly similar SREBP-1c, demonstrated that only a few genes were affected. The only downregulated genes directly linked to lipid metabolism were Srebf1 (which encodes SREBP-1) and Acacb (which encodes acetyl coenzyme A [acetyl-CoA] carboxylase 2 [ACC2], a critical regulator of fatty acyl-CoA partitioning between cytosol and mitochondria). ACC2 regulation is particularly important during food restriction. Similar to Acacb knockout mice, SREBP-1a-deficient mice have lower hepatic triglycerides and higher serum ketones during fasting than wild-type mice. SREBP-1a and -1c have identical DNA binding and dimerization domains; thus, the failure of the more abundant SREBP-1c to substitute for activating hepatic ACC2 must relate to more efficient recruitment of transcriptional coactivators to the more potent SREBP-1a activation domain. Our chromatin immunoprecipitation results support this hypothesis.
Im
Seung-Soon
SS
Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697-3900, USA.
Hammond
Linda E
LE
Yousef
Leyla
L
Nugas-Selby
Cherryl
C
Shin
Dong-Ju
DJ
Seo
Young-Kyo
YK
Fong
Loren G
LG
Young
Stephen G
SG
Osborne
Timothy F
TF
D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D004032:Diet; D004789:Enzyme Activation; D005227:Fatty Acids / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046228:Microarray Analysis; D016297:Mutagenesis, Site-Directed; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*
D005227:Fatty Acids; D020033:Protein Isoforms; D051780:Sterol Regulatory Element Binding Protein 1; C498191:Acacb protein, mouse; D000103:Acetyl-CoA Carboxylase