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Dietary Energy Restriction in Mice Negatively Regulates Hepatic Glucose-Regulated Protein 78 (GRP78) Expression at the Posttranscriptional Level^1,2,

Department of Biochemistry, University of California at Riverside, Riverside, CA 92521 ^* Department of Pathology, School of Medicine, University of California at Los Angeles, Los Angeles, CA 90024

Dietary energy restriction delays age-related physiologic changes, increases maximum life span, and reduces cancer incidence. We showed previously that 50% energy restriction in mice reduces hepatic expression of glucose-regulated protein mRNA by 50 to 80%. Changes in glucose-regulated protein 78 (GRP78) levels can either decrease or increase the rate of secretion of specific proteins. Therefore, energy restriction probably produces a global change in the spectrum of proteins secreted by the liver. These studies were initiated to investigate the molecular basis for the negative regulation of the gene. By use of transfection and nuclear run-on techniques, the strong induction of GRP78 gene transcription in cultured cells subjected to acute, extreme glucose deprivation has been well characterized. However, negative regulation of GRP78 gene expression in vivo by energy restriction is not as well understood. In our studies, a reduction in GRP78 protein levels determined using Western blotting closely paralleled a reduction in hepatic GRP78 mRNA measured by Northern and dot blotting. In each case the changes were statistically significant. This close correspondence indicates that energy restriction does not influence the translation rate or the stability of GRP78 protein. No statistically significant difference in the rate of transcription of the gene was detected in energy-restricted mice by use of transcription run-on assays. These results strongly suggest that energy restriction results in destabilization of GRP78 mRNA, thereby repressing hepatic expression of the gene.

KEY WORDS: • energy restriction • glucose regulated protein 78 • aging • mice • posttranscriptional regulation • mRNA stability

¹ Supported by Public Health Service grant AG00424 from the National Institutes of Health.

² 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 USC section 1734 solely to indicate this fact.

³ To whom correspondence and reprint requests should be addressed.

Manuscript received 16 August 1995. Revision accepted 2 November 1995.

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