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Biochemical, Molecular, and Genetic Mechanisms

Several Transcription Factors Are Recruited to the Glucose-6-Phosphatase Gene Promoter in Response to Palmitate in Rat Hepatocytes and H4IIE Cells¹

Departments of ² Nutrition, ³ Biochemistry, and ⁴ Physiology-Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH, 44106-4935 and the ⁵ Department of Biomedical Sciences, Meharry Medical College, Nashville, TN 37208-3599

^* To whom correspondence should be addressed. E-mail: duna.massillon{at}case.edu.

Fatty acids and glucose are strong modulators of the expression of glucose-6-phosphatase (Glc-6-Pase), an enzyme that plays a key role in glucose homeostasis. PUFA inhibit, whereas SFA and monounsaturated fatty acids induce the expression of the Glc-6-Pase gene. Palmitate and oleate are the most abundant fatty acid species in circulation during food deprivation in mammals. Although dietary fats have been shown to modulate the expression of genes involved in both lipid and carbohydrate metabolism in liver, little is known regarding the molecular mechanism of transcriptional response of the Glc-6-Pase gene to long-chain fatty acids. Using H4IIE hepatoma cells and hepatocytes from adult rats, we investigated the mechanism of the induction of this gene by palmitate and oleate. Both of these fatty acids stimulated Glc-6-Pase gene transcription but did not affect the stability of its mRNA. In transient transfection assays, transcription from the Glc-6-Pase gene promoter was markedly enhanced by both palmitate and oleate but not by arachidonate. Chromatin immunoprecipitation analysis was used to show that palmitate induced the recruitment of an array of transcription factors viz hepatic nuclear factor(NF)-4, CAAT/enhancer binding proteinß, PPAR, chicken ovalbumin upstream promoter transcription factor (COUP-TF), cAMP regulatory element binding protein, and NF-B to this gene promoter. Although it is presently unclear how these various transcription factors interact at this promoter, the data are consistent with the view that multiple regulatory elements in the Glc-6-Pase gene promoter are responsible for the modulation of gene transcription by fatty acids.

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