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Group VIA calcium‐independent phospholipase A2 as a novel regulator of sterol regulatory element‐binding proteins
Author(s) -
Wilkins W Palmer,
Barbour Suzanne E
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a610
Subject(s) - sterol regulatory element binding protein , transcription factor , chemistry , endogeny , transcription (linguistics) , biochemistry , microbiology and biotechnology , phospholipase c , sterol , phospholipase , gene , biology , enzyme , cholesterol , linguistics , philosophy
Sterol regulatory element‐binding proteins (SREBP) are transcription factors that regulate genes involved in lipid metabolism. SREBP undergoes posttranslational processing from an inactive precursor to an active mature form. Exogenous unsaturated fatty acids (UFA) suppress SREBP processing, expression and SREBP‐mediated gene expression. To date, an endogenous source of UFA capable of modulating SREBP remains elusive. Group VIA calcium‐independent phospholipase A 2 (iPLA 2 ) releases UFA from the sn‐2 position of glycerophospholipids and is localized to the same compartment as precursor SREBP. We hypothesize that iPLA 2 provides endogenous UFA that suppress SREBP‐mediated transcription. siRNA and chemical inhibitors were used to suppress iPLA 2 and plasmid and adenovirus strategies were used to overexpress iPLA 2 in CHO and HepG2 hepatoma cells. iPLA 2 inhibition increased both SREBP expression and SREBP‐mediated transcription. In contrast, iPLA 2 overexpression attenuated SREBP expression and SREBP‐mediated transcription. The decline in SREBP correlated with reduced expression of SREBP target genes and attenuated fatty acid synthesis in HepG2 cells. These data support the hypothesis that iPLA 2 generates endogenous UFA that limit SREBP function and suggest that this enzyme may be a target for treatment of lipid disorders. Supported by NIH/NINDS F31 NS05109, NSF MCB 0212213, and NSF MCB 0544068.