Nutrients and environmental factors as regulators of gene expression

Eva Enmark,Jan-Åke Gustafsson

doi:10.1080/110264802753704082

Abstract

Several nuclear receptors bind substances in the diet or metabolites of dietary substances. This makes nuclear receptors a fascinating link between nutrition, toxicology, endocrinology and molecular biology. Nuclear receptor ligands may broadly be divided into two groups. The first group consists of steroid and thyroid hormones, and compounds that constitute intermediates in different biosynthetic pathways in steroid hormone, sterol and bile acid biosynthesis. The second group consists of the very diverse array of compounds that, with no or minor modifications, directly originate from foods, drugs or environmental pollutants. This review summarizes recent results on nuclear receptors with an emphasis on those with ligands of dietary relevance. The finding that several dietary compounds regulate gene expression in the same manner as steroid hormones has provided tools to help unravel molecular secrets and mechanisms behind many diet-associated diseases such as diab etes and obesity. Keywords: Cholesterol, fatty acid, nuclear receptor, orphan receptor, phyto-oestrogen, vitamin.

Highlights

Nuclear receptors constitute a large group of transcription factors which are involved in many important biological processes, e.g. embryonic development, fertility and regulation of metabolism
A measure of their importance is the interest these receptors attract from the pharmaceutical industry, as targets for drugs directed against diseases such as diabetes, cancer and hypercholesterolaemia
Nuclear receptors have turned out to be of interest to endocrinologists, pharmacologists and medicinal chemists, and to toxicologists and nutritionists

Summary

Introduction

Nuclear receptors constitute a large group of transcription factors which are involved in many important biological processes, e.g. embryonic development, fertility and regulation of metabolism. Feeding a diet containing high levels of cholesterol to mice carrying these mutations showed that the LXR-a knockout mice rapidly developed fatty liver due to defective clearance of cholesterol from this tissue [8], whereas inactivation of LXR-b, which has a very similar ligand-binding speci city to LXR-a, does not lead to any apparent liver phenotype [9] It is not yet known whether there are genes that are uniquely regulated by only one of the receptor subtypes. It is expressed mainly in liver, heart, kidney and intestines, and a recently developed PPAR-a knockout mouse has provided important information about the function of this PPAR isoform Studies of this mouse strain have shown that PPAR-a is involved in the regulation of several hepatic peroxisomal enzymes (acyl-CoA oxidase, bifunctional enzyme, thiolase) and microsomal enzymes, as well as certain apolipoproteins and fatty acid transport proteins [22]. It has been shown that a subset of xenobiotic ligands may activate both CAR and PXR, adding even further complexity to the topic of regulation of drug metabolism [49]

Conclusion

Giguere V

Findings

43. Wynne-Edwards KE