Lipidgene interactions diet and health

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D. Lairon and R. P. Pianeils, INSERM, France

3.1 Introduction

Dietary patterns, for about 150 000 years, have reflected a hunter-gatherer way of life that merely sustained scarce human populations of Homo sapiens. Depending on the seasons, there might be predominance of either animal or plant foods, with consequently large seasonal variations in nutrient intakes (Cordain et al., 2000). Although it is difficult to get exact figures, it is estimated that fat intake was low, while carbohydrate and protein intakes were high in the Palaeolithic stone age. This primitive lifestyle has been significantly modified by the intensification of agriculture that progressively spread out over the world and permitted a huge increase in population. From 10 000 BC to the last century, nutrient intakes changed and worldwide figures currently estimate ranges of intakes to be 10-17% of energy for protein, 40-60% of energy for carbohydrate and 20-50% of energy for fat.

During the last century, new techniques for the production of food facilitated an exponential increase in population and the lengthening of average lifespan. However, this improvement in food availability, along with changes in lifestyles toward less physical activity, but perhaps with more 'stress', was also accompanied by substantial changes in dietary patterns. Indeed, at least in industrialized countries, energy intake increased, and the contribution of dietary fat (40-50% energy), especially saturated fatty acids, became more and more important. At the same time, the prevalence of metabolic diseases (obesity, metabolic syndrome, diabetes and subsequently cardiovascular diseases) dramatically increased. Because of the economic costs of these conditions, we have been driven to ask whether changes in diets, and dietary fat more particularly, could, at least in part, be responsible for this significant rise in metabolic diseases.

Almost all metabolic diseases involve serious disturbances in lipid metabolism, and a wealth of epidemiologic studies have identified alterations in plasma lipid levels as major risk markers for cardiovascular diseases (CVD) as well as type 2 diabetes or obesity. This observed correlation between plasma lipid alterations and chronic diseases has raised the question of the role played by dietary fat in their genesis, and it is now usual to recommend dietary measures to reduce the prevalence of such diseases. Nevertheless, the use of diet to reduce risk of chronic disease raises a number of important questions, since most studies have shown that the responsiveness to diets is a complex process, dependent on both individual (genetic) features and interactions between nutrients.

Responsiveness to a change in dietary pattern depends on the activity of several proteins, all intricately involved in complex metabolic pathways. We know that, though all human beings belong to the same species, Homo sapiens sapiens, minor alterations in gene structures could be responsible for determining differences between subjects. Indeed, every gene encoding a protein involved in response to diets can be polymorphic, the product of a given allele acting differently from the product of another allele. The overall response resulting from the addition of these slight differences may lead to an important variability from subject to subject, which is particularly well demonstrated during intervention studies. In such studies, for an identical change in diet, a majority of subjects (the responders) display a large modification of a parameter, while a minority of subjects (the non-responders) do not exhibit any marked change or may even modify this parameter in the opposite direction. However, the same modification of the diet would lead to a different response pattern when another parameter is studied.

To date gene-diet interaction studies are aimed at associating with each of these groups, responders or non-responders, a significant distribution of allelic variants in candidate gene locus. In most cases these candidate genes will be those encoding apolipoproteins and enzymes involved in lipid metabolism, those involved in lipid signalling and those coding for the transcriptional factors controlling the expression of enzymes, receptors, apolipoproteins, etc., involved in regulating lipid metabolism. Over time, several single nucleotide polymorphisms (SNPs) have been identified and associated with particular responses to changes in nutrients or in dietary patterns.

Nowadays, in light of the Human Genome Project, a wealth of genetic data is being generated, thanks to new methodological tools allowing easy and cost-sensitive determination of a large number of gene polymorphisms. In addition, owing to the development of informatics tools, these data can be more and more easily connected to physiological information. This opens a new era where studies dedicated to interactions between diets; metabolic parameters, disease risk factors and gene polymorphisms can be carried out on small or large groups of healthy subjects or patients.

In this chapter, we will first review the available literature data discussing some polymorphisms of selected key proteins involved in lipid and lipoprotein metabolism. We will describe successively their responsiveness to dietary fatty acids, then to dietary cholesterol and finally the metabolic syndrome. We shall then focus on the mechanisms of regulation of gene expression by fat, a process that involves, for a large part, nuclear receptors. This extensively studied gene family of transcription factors provides a heuristic paradigm of regulation of gene expression. Finally, we will suggest what can be deduced currently from these studies in terms of 'optimal' dietary fat and possible ways toward a better knowledge of diet-genetic background interactions.

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