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J. Biol. Chem., Vol. 278, Issue 42, 40694-40701, October 17, 2003

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Regulation of Glucose-6-phosphatase Gene Expression in Cultured Hepatocytes and H4IIE Cells by Short-chain Fatty Acids

ROLE OF HEPATIC NUCLEAR FACTOR-4^*

Duna Massillon, Recipient of a Case Western Reserve University Faculty Fellowship Award from the Mount Sinai Health Care Foundation, Cleveland, OH.  , Ifeanyi J. Arinze ¶, Chuan Xu  and Frederic Bone ||

From the Departments of Nutrition and ^||Physiology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4935 and the ^¶Department of Biochemistry, Meharry Medical College, Nashville, Tennessee 37208-3599

Mechanisms underlying dietary nutrient regulation of glucose-6-phosphatase (Glc-6-Pase) gene expression are not well understood. Here we investigated the effects of short-chain fatty acids on the expression of this gene in primary cultures of rat hepatocytes and H4IIE hepatoma cells. Propionate, butyrate, valerate, and caproate induced severalfold increases in the expression of Glc-6-Pase mRNA. In reporter gene assays, propionate, valerate, caproate, and also octanoate increased Glc-6-Pase promoter activity by 6-16-fold. Butyrate, by itself, had little or no effect on promoter activity, but it induced a robust increase (45-fold) in promoter activity in cells co-transfected with a plasmid expressing the transcription factor HNF-4 ( isoforms of hepatic nuclear factor 4). HNF-4 also enhanced promoter activity induced by other short-chain fatty acids. A dominant negative form of HNF-4 abrogated the fatty acid-induced promoter activity, a finding that accentuates a role for HNF-4 in the transcription process studied here. In cells transfected with HNF-4, short-chain fatty acids and trichostatin A, an inhibitor of histone deacetylase, synergistically enhanced promoter activity, suggesting that hyperacetylation of histones is an important component of the transactivation of the Glc-6-Pase gene promoter by HNF-4. Region-751/-466 of this promoter contains seven putative HNF-4-binding motifs. Binding of HNF-4 to this region was confirmed by electrophoretic mobility shift and chromatin immunoprecipitation assays, indicating that HNF-4 is recruited to the Glc-6-Pase gene promoter during short-chain fatty acid-induced transcription from this promoter.

Received for publication, March 27, 2003 , and in revised form, July 31, 2003.

^* This work was supported by a grant (to D. M.) from the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Nutrition, Case Western Reserve University School of Medicine, 10900 Euclid Ave., Cleveland, OH 44106-4935. Tel.: 216-368-2135; Fax: 216-368-6644; E-mail: dxm71{at}po.cwru.edu.

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