DIETARY POLYUNSATURATED FATTY-ACIDS INTERFERE WITH THE INSULIN/GLUCOSE ACTIVATION OF L-TYPE PYRUVATE-KINASE GENE-TRANSCRIPTION

被引:97
作者
LIIMATTA, M
TOWLE, HC
CLARKE, S
JUMP, DB
机构
[1] MICHIGAN STATE UNIV, DEPT PHYSIOL, E LANSING, MI 48824 USA
[2] MICHIGAN STATE UNIV, DEPT BIOCHEM, E LANSING, MI 48824 USA
[3] UNIV MINNESOTA, DEPT BIOCHEM, MINNEAPOLIS, MN 55455 USA
[4] COLORADO STATE UNIV, DEPT FOOD SCI & HUMAN NUTR, FT COLLINS, CO 80523 USA
关键词
D O I
10.1210/me.8.9.1147
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
L-type pyruvate kinase (L-PK) is a key glycolytic enzyme regulating the flux of metabolites through the pyruvate-phosphoenolpyruvate cycle (1). The regulation of L-PK is complex involving both hormones and nutrients. We have found that feeding rats diets containing polyunsaturated fatty acids (PUFA) significantly inhibits hepatic pyruvate kinase enzyme activity (>60%) and suppresses mRNA(PK) abundance (>70%). Studies with primary hepatocytes indicate that PUFA act directly on hepatocytes. Specifically, arachidonic (20:4, omega 6) and eicosapentaenoic (20:5, omega 3) acid suppressed both mRNA(PK) levels and the activity of a transfected PKCAT (-4300/+12) fusion gene by >70%. This is due to an inhibition of the insulin/glucose-mediated transactivation of L-PKCAT. Deletion analysis localized PUFA-regulated cis-acting elements to a region within the L-PK proximal promoter, i.e. between -197 and -96 base pairs. This region binds two transcription factors involved in the hormone/nutrient regulation of L-PK gene transcription, i.e. a major late transcription factor-like factor and HNF-4. Linker scanning mutation analysis localized the PUFA-regulated cis-acting elements to the vicinity of the HNF-4 binding site. Thus, PUFA-regulated factors abrogate the insulin/glucose activation of L-PK gene transcription by targeting the HNF-4 elements. These studies suggest that PUFA may have significant effects on hepatic carbohydrate metabolism by inhibiting the L-PK side of the pyruvate-phosphoenolpyruvate cycle.
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页码:1147 / 1153
页数:7
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