Nutrients are capable of modulating specific gene expression. This initially adaptive process could be the origin of certain pathologies but could also be used in the future for therapeutic means.

Living creatures are in constant interaction with their environment. Recent progress in molecular biology show that food may act on the expression of a number of genes, leading to an adaptation mechanism that can vary between individuals.

The 50 to 100 000 genes that constitute a cell's genome are not expressed at the same time. Their expression is dependent on the cell type (some pulmonary cells won't express the same genes as hepatocytes), on the stage of cellular differentiation and on the environment. The expression of a gene must therefore be controlled. The regulation of the transcription (see box) of one gene is a tightly controlled system.

Some examples show that nutrients such as glucose, cholesterol and fatty acids can modify the transcription of genes that code for proteins (enzymes, hormones) involved in their metabolism.

Example of glucokinase and phosphoenolpyruvate carboxykinase:
The liver of mammals has the property to capture and metabolise glucose that is delivered by the portal vein. Glucokinase is an enzyme involved in this process and is needed only in an individual who regularly absorbs carbohydrate. However, the liver also has the property to synthesise glucose de novo (gluconeogenesis) when the intestine stops delivering any. The liver then pours glucose into the circulation for organs that continuously need it, such as the brain. Phosphoenolpyruvate carboxykinase (PEPCK), is an enzyme involved in gluconeogenesis, and is necessary in case of shortage in glucose. Figure 1 illustrates the modulation of glucokinase and PEPCK mRNA in a carbohydrate fasting/refeeding cycle in the rat. After 24h of fasting, PEPCK mRNA is abundant in the liver and glucokinase mRNA is undetectable. The gene of PEPCK is transcribed but not the one of glucokinase. The liver is in "glucose production" mode.

In the minutes following the absorption of a carbohydrate meal, PEPCK mRNA decrease quickly and glucokinase mRNA appear. The gene of glucokinase is then transcribed but the gene of PEPCK is not anymore. The liver is in "use of glucose" mode. Specific mechanisms are also triggered to degrade PEPCK mRNA.

This example illustrates how our genetic program answers to our nutritional environment. There are other systems of regulation: they don't all involve transcription but they may modify the activity of a protein already synthesised, which is a very fast mechanism (a few seconds). Although transcription of a gene can be quickly modulated, several minutes to several hours are necessary between the triggering of gene inscription and the synthesis of the corresponding protein in sufficient amount. Gene regulation can be considered like a longer-term adaptive mechanism, which prepares the organism to the repetition of nutritional events.

Nutrients can have a direct or an indirect effect:
In unicellular organisms (bacteria, yeast), the direct effect of nutrients on gene expression, without hormonal relay, has been known for a long time. In multicellular organisms, it was thought that the effect of nutrients was modulated by hormonal variations. In fact, some genes are controlled by hormones. In the example above, PEPCK gene is activated by glucagon and is inhibited by insulin, whereas the glucokinase gene is activated by insulin and is inhibited by glucagon. Following carbohydrate absorption, insulin is raised and glucagon lowered as the reverse situation occurs during fasting.

Recently, it was found that as in primitive organisms, nutrients are also able to control gene expression without hormonal relay in complex organisms.

Studies conducted in animal models show that all types of nutrients, including carbohydrates, lipids, amino acids, vitamins and minerals, are able to modulate gene expression.

Carbohydrates:
In beta cells of the pancreas islets of Langherans, glucose activates not only the secretion of insulin but also the transcription of the insulin gene. Glucose initiates the transfer of a transcription factor from the cytoplasm to the nucleus, necessary to the transcription of the insulin gene.
In the liver, during the absorption of large quantities of glucose, part of it is converted into fatty acids through lipogenesis (this is the metabolic way to obtain foie gras by force-feeding geese with corn!). In vitro glucose concentrations in the range of 2-3 g/l (equivalent to those of portal venous blood) can activate gene transcription of fatty acid synthase and acetyl-CoA carboxylase, two key enzymes of this metabolic pathway. The mechanism involved is not yet identified.

Cholesterol:
Necessary to cell life, cholesterol can be from endogenous origin (synthesis) or from exogenous origin following capture of low-density lipoproteins (LDL) rich in cholesterol. When a cell contains sufficient quantities of cholesterol, genes coding for enzymes of cholesterol synthesis and for the membrane LDL-receptor are not expressed.

On the other hand, if quantities of cellular cholesterol become insufficient, the expression of these genes is activated. These molecular mechanisms are now well understood.

Cellular concentrations of mRNA can be measured by a technique called " Northern-blot ". mRNA is extracted, set on a special membrane and exposed (hybridised) to a probe consisting of a complementary sequence of the mRNA of interest, artificially synthesised and radiolabeled. The membrane is then put in contact with a photographic film that will be printed by the radioactive probe. The intensity of the autoradiography is then proportional to the quantity of mRNA.
Figure 1

Fatty acids:
Fatty acids can activate the expression of genes coding for some of their carriers in the intestine and in the adipose tissue, or for proteins involved in their metabolism. This mechanism of action implies that these fatty acids bind to a nuclear transcription factor called PPAR (" Peroxisome Proliferator Activated Receptor "). The PPAR is also involved in the differentiation of pre-adipocytes into adipocytes. It is therefore not excluded that fatty acids can play a role in modulating the number of adipocytes.
On the other hand, polyunsaturated fatty acids can inhibit the expression of gene involved in lipogenesis when present in very small quantities in the diet of rodents. The mechanism remains unknown.

Epidemiological studies suggest that a mother's diet during pregnancy or the diet of an infant or young child could affect the prevalence of syndromes during adulthood, such as obesity, diabetes, hypertension or cardiovascular diseases. Foetal and neonatal life could represent key periods during which the effect of nutrients on gene expression would definitively modify the future of an individual. Hence, a high fat diet during childhood could lead to a massive differentiation of pre-adipocytes into adipocytes, laying the ground for potential future obesity.

Although all mechanisms and genes implied are not identified, these examples show how nutrients can regulate gene expression. It is mainly an adaptive phenomenon. However, it is possible that the genome of an individual doesn't allow these adaptive responses to food and even lead to deleterious metabolic replies.
We may consider that if these processes are altered, they can contribute to certain nutritional pathologies (obesity for example), thus opening new fields of investigation for genetic studies.
Finally, by introducing specific nutrients or derivative of nutrients in food, we could consider using genetic regulation as a therapeutic mean. Will nutrition in the 21st century be molecular?

Dr. Pascal FERRE
INSERM U. 465, Paris,

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