Citrate cleavage in adipose tissue.

Kornacker, Melodee S.; Ball, Eric G.

doi:10.1073/pnas.54.3.899

Cited by 104 publications

(18 citation statements)

References 14 publications

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“…ACLY catalyzes the formation of acetyl-CoA from citrate and CoA and thus provides the first building block for de novo lipid synthesis (28,29). FASN is a multifunctional enzyme that performs seven sequential reactions to convert acetyl-CoA and malonyl-CoA to palmitate (30 -32).…”

Section: Discussionmentioning

confidence: 99%

Identification of a New Fatty Acid Synthesis-Transport Machinery at the Peroxisomal Membrane

Hillebrand

Gersting

Lotz-Havla

et al. 2012

Journal of Biological Chemistry

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Background: Dysfunction of the peroxisomal ABC transporter ALDP and elevated very long chain fatty acids are the hallmark of X-ALD. Results: Peroxisomal ABC transporters interact with proteins functioning in fatty acid synthesis and activation. Conclusion: We identified a new fatty acid synthesis-transport machinery adapted to different chain lengths and metabolic conditions. Significance: This machinery extends the knowledge on peroxisomal ␤-oxidation and X-ALD pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Identification of a New Fatty Acid Synthesis-Transport Machinery at the Peroxisomal Membrane

Hillebrand

Gersting

Lotz-Havla

et al. 2012

Journal of Biological Chemistry

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“…1 is a cytosolic enzyme that catalyzes the cleavage of citrate into oxaloacetate and acetyl-CoA (1). In liver and adipose tissue, this enzyme plays an important role in supplying acetyl-CoA for both fatty acid and cholesterol synthesis (2).…”

Section: Atp Citrate-lyase (Acl)mentioning

confidence: 99%

The Roles of Sterol Regulatory Element-binding Proteins in the Transactivation of the Rat ATP Citrate-Lyase Promoter

Moon¹,

Lee²,

Sw³

et al. 2000

Journal of Biological Chemistry

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ATP citrate-lyase (ACL) is a key enzyme supplying acetyl-CoA for fatty acid and cholesterol synthesis. Its expression is drastically up-regulated when an animal is fed a low fat, high carbohydrate diet after prolonged fasting. In this report, we describe the role of sterol regulatory element-binding proteins (SREBPs) in the transactivation of the rat ACL promoter. ACL promoter activity was markedly stimulated by the overexpression of SREBP-1a and, to a lesser extent, by SREBP-2 in Alexander human hepatoma cells. The promoter elements responsive to SREBPs were located within the 55-base pair sequences from ؊114 to ؊60. The gel mobility shift assay revealed four SREBP-1a binding sites in this region. Of these four elements, the ؊102/؊94 region, immediately upstream of the inverted Y-box, and the ؊70/؊61 region, just adjacent to Sp1 binding site, played critical roles in SREBPs-mediated stimulation. The mutation in the inverted Y-box and the coexpression of dominant negative nuclear factor-Y (NF-Y) significantly attenuated the transactivation by SREBP-1a, suggesting that NF-Y binding is a prerequisite for SREBPs to activate the ACL promoter. However, the multiple Sp1 binding sites did not affect the transactivation of the ACL promoter by SREBPs. The binding affinity of SREBP-1a to SREs of the ACL promoter also was much higher than that of SREBP-2. The transactivation potencies of the chimeric SREBPs, of which the activation domains (70 amino acids of the amino terminus) were derived from the different species of their carboxyl-terminal region, were similar to those of SREBPs corresponding to their carboxyl termini. Therefore, it is suggested that the carboxyl-terminal portions of SREBPs containing DNA binding domains are important in determining their transactivation potencies to a certain promoter. ATP citrate-lyase (ACL)1 is a cytosolic enzyme that catalyzes the cleavage of citrate into oxaloacetate and acetyl-CoA (1). In liver and adipose tissue, this enzyme plays an important role in supplying acetyl-CoA for both fatty acid and cholesterol synthesis (2). As the specific inhibition of ACL in rats significantly decreases the plasma levels of triacylglycerol and cholesterol, ACL is expected to be a potential target for hypolipidemic intervention (3, 4). The activity of ACL is mainly regulated at the level of transcription by diet regimen and insulin, like other lipogenic enzymes, such as fatty acid synthase and acetyl-CoA carboxylase (5). The sequences of the 5Ј flanking region of the ACL gene are highly conserved in humans and rats, whereas there is no homology in the regions of the 5Ј untranslated region and the first intron, suggesting that transcription is regulated in the same manner in these two species (6, 7). Although ACL plays an important role in fatty acid and cholesterol biosynthesis and is highly controlled by diet at the transcription level, studies on the structure and function of this promoter have been very limited thus far.SREBPs are the transcription factors that regulate the transcription of ma...

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“…In present study, ACL minimal promoter -60/+67, in place of artificial TATA promoter, was used to increase the basal expression. ACL is a cytosolic enzyme that catalyzes the cleavage of citrate into oxaloacetate and acetyl-CoA (Kornacker and Ball, 1965). The activity of ACL is mainly regulated at transcriptional level in response to dietary status and insulin, like other lipogenic enzymes (Kim et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

Development of ligand-dependent regulatory system and its application to gene therapy of insulin-dependent diabetes mellitus

Kim¹,

Kim²,

Lee³

et al. 2006

Exp Mol Med

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To develop an inducible expression system, the enhanced artificial nuclear receptors and target reporters were constructed. Artificial nuclear receptors were generated by fusing three domains, consisting of DNA-binding domain (DBD) of GAL4, ligand binding domain (LBD) of progesterone or estrogen receptor, and activation domain (AD) of VP16, sterol regulatory element binding protein (SREBP)-1a, or SREBP-2. The activation domain of SREBP-1a showed most potent transcriptional activity. The maximal level of target reporter gene expression was extremely elevated by the usage of ATP citrate-lyase (ACL) minimal promoter -60/+67 in place of artificial TATA promoter, while the SV40 enhancer severely increased the basal transcription in the absence of ligand. The induction system, developed in the present study, was applied to cell therapy, resulting in successful induction of single-chain insulin analogue (SIA) gene expression to correct the hyperglycemia in diabetic animals. By means of subcutaneous cell therapy, the SIA gene expression rapidly occurred after the local topical application of ligand. These results suggest that our system represents a powerful tool for transcriptional regulation of target gene that can be used for diverse applications, ranging from basic research to gene therapy.

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Citrate cleavage in adipose tissue.

Cited by 104 publications

References 14 publications

Identification of a New Fatty Acid Synthesis-Transport Machinery at the Peroxisomal Membrane

Identification of a New Fatty Acid Synthesis-Transport Machinery at the Peroxisomal Membrane

The Roles of Sterol Regulatory Element-binding Proteins in the Transactivation of the Rat ATP Citrate-Lyase Promoter

Development of ligand-dependent regulatory system and its application to gene therapy of insulin-dependent diabetes mellitus

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