Identification of a mammalian long chain fatty acyl elongase regulated by sterol regulatory element-binding proteins.
Fatty acids are synthesized de novo from acetyl-CoA and malonyl-CoA through a series of reactions mediated by acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). In rodents, the principal fatty acid produced by FAS is palmitic acid (16:0). Sterol regulatory element-binding proteins (SREBPs) enhance the transcription of many genes responsible for fatty acid synthesis. In transgenic mice that overexpress SREBPs in liver, the rate of fatty acid synthesis is markedly increased, owing to the activation of these biosynthetic genes, which include ATP citrate lyase, ACC, FAS, and stearoyl-CoA desaturase. The fatty acids that accumulate in livers of SREBP transgenic mice are 18 carbons rather than 16 carbons in length, suggesting that the enzymes required for the elongation of palmitic to stearic acid may be induced. Here, we report the cDNA cloning of a murine long chain fatty acyl elongase (LCE) that was identified initially by oligonucleotide array analysis of mRNA from SREBP transgenic mouse livers. LCE mRNA is highly expressed in liver and adipose tissue. The cDNA encodes a protein of 267 amino acids that shares sequence identity with previously identified very long chain fatty acid elongases. Cells that overexpress LCE show enhanced addition of 2-carbon units to C12-C16 fatty acids. We provide evidence that LCE catalyzes the rate-limiting condensing step in this reaction. The current studies suggest that mouse LCE expression is increased by SREBPs and that the enzyme is a component of the elusive mammalian elongation system that converts palmitic to stearic acid.
Moon
Y A
YA
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9046, USA.
Shah
N A
NA
Mohapatra
S
S
Warrington
J A
JA
Horton
J D
JD
D000123:Acetyltransferases / Q000737:chemistry*; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D000081031:Fatty Acid Elongases; D015723:Gene Library; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008099:Liver / Q000378:metabolism; D008297:Male; D008316:Malonyl Coenzyme A / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D008862:Microsomes, Liver / Q000378:metabolism; D008969:Molecular Sequence Data; D009249:NADP / Q000494:pharmacology; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D019308:Palmitic Acid / Q000378:metabolism / Q000494:pharmacology; D010171:Palmitoyl Coenzyme A / Q000494:pharmacology; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013229:Stearic Acids / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1; D013379:Substrate Specificity; D013997:Time Factors; D014018:Tissue Distribution; D014157:Transcription Factors; D014162:Transfection
D000596:Amino Acids; D022762:CCAAT-Enhancer-Binding Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; C497387:SREBF1 protein, human; C497388:Srebf1 protein, mouse; D013229:Stearic Acids; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D010171:Palmitoyl Coenzyme A; D019308:Palmitic Acid; C031183:stearic acid; D008316:Malonyl Coenzyme A; D009249:NADP; D000123:Acetyltransferases; D000081031:Fatty Acid Elongases