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Nutrient Regulation of Gene Expression¹

Centre de Recherche sur l'Endocrinologie Moleculaire et le Developpement, Centre National de la Recherche Scientifique, 9, Rue Jules Hetzel, 92190 Meudon, France

Abstract

This paper reviews recent evidence for the roles and mechanisms of action of energy substrates in the mediation of abrupt changes in gene expression of key enzymes involved in regulation of hepatic fatty acid oxidation and ketogenesis during the perinatal transition, and of lipogenesis in adipose and liver during the weaning transition in young rats. Rapid and marked postnatal increases in hepatic catabolism of long-chain fatty acids (LCFA) are associated with increased gene transcription of the rate-limiting enzyme for fatty acid oxidation, mitochondrial carnitine palmitoyltransferase I (CPT I), and increased mRNA for the rate-limiting enzyme for ketogenesis, mitochondrial 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) synthase. In vitro evidence strongly indicates that in both cases, gene expression in vivo is stimulated by increased plasma concentrations of glucagon, via the cAMP system, and LCFA. For stimulation of CPT I expression, at least, it seems that LCFA must first be activated to their CoA esters, and that the effects of cAMP and LCFA occur by different mechanisms. The transition from a high-fat, low-carbohydrate to a high-carbohydrate, low-fat diet at weaning causes large increases in activity of several lipogenic enzymes, including fatty acid synthase (FAS) and acetyl-CoA carboxylase, in adipose tissue and liver, preceded by increased levels of mRNA for these enzymes. In cultured adipocytes and hepatocytes from suckling rats, FAS expression is strongly stimulated by glucose after its metabolism to glucose-6-phosphate. Insulin alone has little direct effect but potentiates the action of glucose in both cell types. Early evidence suggests that the FAS gene contains a glucose response element resembling that in better-characterized, glucose-responsive genes such as Spot 14, but mechanisms of glucose signal transduction are unknown. In summary, LCFA and glucose are important regulatory factors for transcriptional control of CPT I and HMG-CoA synthase in neonatal liver and of lipogenic enzymes in liver and adipose tissue of the newly weaned animal.

Key Words: Neonatal Rat • Liver • Lipid Metabolism • Regulatory Enzyme Transcription • Energy Substrates

¹ We thank J. D. McGarry, F. Hegardt, and A. G. Goodridge for kindly providing us with the cDNA probes used in these studies. The original work presented in this paper was supported in part by grants from the "Ministère de la Recherche et de la Technologie" (no. 88-G-0119, 90-G-0292, 92-G-0499), Eridiana Béghin-Say, Paris and "Fondation pour la Recherche Médicale," France.

² To whom correspondence should be addressed.

³ Unité 341 INSERM, Hôtel-Dieu, 1 Place du Parvis Notre-Dame, 75004 Paris, France.

⁴ Unité 342 INSERM, Hôpital Saint-Vincent-de-Paul, 82 Avenue Denfert-Rochereau, 75014 Paris, France.