Essential fatty acid synthesis and its regulation in mammals.
The tissue content of highly unsaturated fatty acids (HUFA) such as arachidonic acid and docosahexaenoic acid is maintained in a narrow range by feedback regulation of synthesis. Delta-6 desaturase (D6D) catalyzes the first and rate-limiting step of the HUFA synthesis. Recent identification of a human case of D6D deficiency underscores the importance of this pathway. Sterol regulatory element binding protein-1c (SREBP-1c) is a key transcription factor that activates transcription of genes involved with fatty acid synthesis. We recently identified sterol regulatory element (SRE) that is required for activation of the human D6D gene by SREBP-1c. Moreover, the same SRE also mediates the suppression of the D6D gene by HUFA. The identification of SREBP-1c as a key regulator of D6D suggests that the major physiological function of SREBP-1c in liver may be the regulation of phospholipid synthesis rather than triglyceride synthesis. Peroxisome proliferators (PP) induce fatty acid oxidation enzymes and desaturases in rodent liver. However, the induction of desaturases by PP is slower than the induction of oxidation enzymes. This delayed induction may be a compensatory reaction to the increased demand of HUFA caused by increased HUFA oxidation and peroxisome proliferation in PP administration. Recent studies have demonstrated a critical role of peroxisomal beta-oxidation in DHA synthesis, and identified acyl CoA oxidase and D-bifunctional protein as the key enzymes.
Nakamura
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Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, 905 S. Goodwin Avenue, Urbana, IL 61801, USA. mtnakamu@uiuc.edu
Nara
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D015067:17-Hydroxysteroid Dehydrogenases; D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000502:physiology; D042962:Acyl-CoA Oxidase; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology*; D004746:Enoyl-CoA Hydratase; D005227:Fatty Acids / Q000096:biosynthesis* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006836:Hydro-Lyases / Q000502:physiology; D008099:Liver / Q000378:metabolism; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000502:physiology; D010088:Oxidoreductases / Q000502:physiology; D064029:Peroxisomal Multifunctional Protein-2; D020025:Peroxisome Proliferators / Q000378:metabolism; D020675:Peroxisomes / Q000378:metabolism; D051381:Rats; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D005227:Fatty Acids; D009097:Multienzyme Complexes; D020025:Peroxisome Proliferators; C497387:SREBF1 protein, human; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D010088:Oxidoreductases; D015067:17-Hydroxysteroid Dehydrogenases; D015094:3-Hydroxyacyl CoA Dehydrogenases; C491286:Hsd17b4 protein, rat; D042962:Acyl-CoA Oxidase; D006836:Hydro-Lyases; D064029:Peroxisomal Multifunctional Protein-2; C104587:HSD17B4 protein, human; D004746:Enoyl-CoA Hydratase