Document Detail

Parallel regulation of sterol regulatory element binding protein-2 and the enzymes of cholesterol and fatty acid synthesis but not ceramide synthesis in cultured human keratinocytes and murine epidermis.
MedLine Citation:
PMID:  9508001     Owner:  NLM     Status:  MEDLINE    
After permeability barrier perturbation there is an increase in the mRNA levels for key enzymes necessary for lipid synthesis in the epidermis. The mechanism(s) responsible for this regulation is unknown. Sterol regulatory element binding proteins-1a, 1c, and -2 (SREBPs) control the transcription of enzymes required for cholesterol and fatty acid t synthesis in response to modulations of sterol levels. We now demonstrate that SREBP-2 is the predominant SREBP in human keratinocytes and murine epidermis, while SREBP-1 is not detected. Sterols regulate SREBP-2 mRNA levels in keratinocytes and the epidermis and the proteolytic cleavage of SREBP-2 to the mature active form in keratinocytes. In parallel to the increase in mature active SREBP, there is a coordinate increase in mRNA levels for cholesterol (HMG-CoA reductase, HMG-CoA synthase, farnesyl diphosphate synthase, and squalene synthase) and fatty acid (acetyl-CoA carboxylase, fatty acid synthase) synthetic enzymes. However, mRNA levels for serine palmitoyl transferase (SPT), the first committed step for ceramide synthesis, do not increase in parallel. The increase of mRNA for enzymes required for epidermal cholesterol and fatty acid synthesis is consistent with both the previously described early increase of cholesterol and fatty acid synthesis after barrier disruption and a role for SREBP-2 in the regulation of cholesterol and fatty acid synthesis for epidermal barrier homeostasis. In contrast, SPT appears to be regulated by different mechanisms, consistent with the different time course of its stimulation after barrier disruption.
I R Harris; A M Farrell; W M Holleran; S Jackson; C Grunfeld; P M Elias; K R Feingold
Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of lipid research     Volume:  39     ISSN:  0022-2275     ISO Abbreviation:  J. Lipid Res.     Publication Date:  1998 Feb 
Date Detail:
Created Date:  1998-04-08     Completed Date:  1998-04-08     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  0376606     Medline TA:  J Lipid Res     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  412-22     Citation Subset:  IM    
Department of Veterans Affairs Medical Center, Department of Dermatology, University of California, San Francisco 94121, USA.
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MeSH Terms
Acetyl-CoA Carboxylase / genetics
Alkyl and Aryl Transferases / genetics
Cells, Cultured
Ceramides / biosynthesis*
Cholesterol / biosynthesis*
DNA-Binding Proteins / genetics*
Epidermis / metabolism*
Farnesyl-Diphosphate Farnesyltransferase / genetics
Fatty Acids / biosynthesis*
Gene Expression Regulation
Hydroxymethylglutaryl CoA Reductases / genetics
Hydroxymethylglutaryl-CoA Synthase / genetics
Keratinocytes / metabolism*
Mice, Hairless
RNA, Messenger / metabolism
Sterol Regulatory Element Binding Protein 2
Transcription Factors / genetics*
Grant Support
Reg. No./Substance:
0/Ceramides; 0/DNA-Binding Proteins; 0/Fatty Acids; 0/RNA, Messenger; 0/SREBF2 protein, human; 0/Srebf2 protein, mouse; 0/Sterol Regulatory Element Binding Protein 2; 0/Transcription Factors; 57-88-5/Cholesterol; EC 1.1.1.-/Hydroxymethylglutaryl CoA Reductases; EC Synthase; EC 2.5.-/Alkyl and Aryl Transferases; EC; EC Farnesyltransferase; EC Carboxylase

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