Acetyl-coenzyme A synthetase is a lipogenic enzyme controlled by SREBP-1 and energy status.
DNA microarray analysis on upregulated genes in the livers from transgenic mice overexpressing nuclear sterol regulatory element-binding protein (SREBP)-1a, identified an expressed sequence tag (EST) encoding a part of murine cytosolic acetyl-coenzyme A synthetase (ACAS). Northern blot analysis of the livers from transgenic mice demonstrated that this gene was highly induced by SREBP-1a, SREBP-1c, and SREBP-2. DNA sequencing of the 5' flanking region of the murine ACAS gene identified a sterol regulatory element with an adjacent Sp1 site. This region was shown to be responsible for SREBP binding and activation of the ACAS gene by gel shift and luciferase reporter gene assays. Hepatic and adipose tissue ACAS mRNA levels in normal mice were suppressed at fasting and markedly induced by refeeding, and this dietary regulation was nearly abolished in SREBP-1 knockout mice, suggesting that the nutritional regulation of the ACAS gene is controlled by SREBP-1. The ACAS gene was downregulated in streptozotocin-induced diabetic mice and was restored after insulin replacement, suggesting that diabetic status and insulin also regulate this gene. When acetate was administered, hepatic ACAS mRNA was negatively regulated. These data on dietary regulation and SREBP-1 control of ACAS gene expression demonstrate that ACAS is a novel hepatic lipogenic enzyme, providing further evidence that SREBP-1 and insulin control the supply of acetyl-CoA directly from cellular acetate for lipogenesis. However, its high conservation among different species and the wide range of its tissue distribution suggest that this enzyme might also play an important role in basic cellular energy metabolism.
Sone
Hirohito
H
Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba 305-8575, Japan.
Shimano
Hitoshi
H
Sakakura
Yuki
Y
Inoue
Noriyuki
N
Amemiya-Kudo
Michiyo
M
Yahagi
Naoya
N
Osawa
Mitsujiro
M
Suzuki
Hiroaki
H
Yokoo
Tomotaka
T
Takahashi
Akimitsu
A
Iida
Kaoruko
K
Toyoshima
Hideo
H
Iwama
Atsushi
A
Yamada
Nobuhiro
N
D000106:Acetate-CoA Ligase / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence / Q000235:genetics; D000821:Animal Feed; D000818:Animals; D001483:Base Sequence / Q000235:genetics; D022762:CCAAT-Enhancer-Binding Proteins / Q000502:physiology*; D003001:Cloning, Molecular; D004247:DNA / Q000235:genetics; D004268:DNA-Binding Proteins / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000378:metabolism; D004734:Energy Metabolism / Q000502:physiology*; D005215:Fasting / Q000502:physiology; D015870:Gene Expression; D007328:Insulin / Q000172:deficiency; D008055:Lipids / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D007328:Insulin; D008055:Lipids; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D004247:DNA; D000106:Acetate-CoA Ligase