Fatty Acids Gene Expression and Coronary Heart Disease CHD

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Anne M. Minihane

University of Reading, Reading, UK

Introduction 182

Fatty Acid Structure and Tissue Sources 182

Metabolism of Fatty Acids 183

Absorption 183

Transport as Lipoproteins 184

Intracellular Metabolism 186

Fatty Acid Regulation of Gene Expression 187

PUFA and Hepatic Lipogenesis 187

PUFA Induction of Lipid Oxidation 189

Fatty Acids and Adipocytes Gene Expression 189

Fatty Acid and Arterial Wall Gene Expression 190

PUFA and Their Cellular Mechanisms of Action 191

Transcription Factors 192

Peroxisome Proliferator-Activated Receptors (PPAR) 192

PPAR Ligands 193 Other Families of Transcription Factors that Mediate the PUFA/PUFA

Derivative Effect on Gene Expression 193

Sterol Regulatory Element-Binding Protein 194

Hepatic Nuclear Receptor-4 (HNF-4) 194

Nuclear Factor-Y (NF-Y) and Nuclear Factor Kappa B (NF-kB) 194

Fatty Acids, Gene Expression, and the Coordination of Glucose and

Insulin Homeostasis and Lipoprotein Metabolism Summary References

196 196

INTRODUCTION

Over 95% of fat in the diet and in the body is present as fatty acids. In addition to meeting 30-40% of total body energy demands in Westernized societies, fatty acids are an integral component of all biological membranes and serves as a precursor for a number of essential compounds in the body such as the hormone-like eicosanoids, which mediate inflammatory and thrombotic processes. Furthermore, in recent years, it has become evident that fatty acids can also act as signalling molecules by serving as ligands for transcriptional factors which modulate gene expression.

Research in this area is in its relative infancy, and has for the most part focussed on the expression of hepatic genes directly involved in fatty acid metabolism or lipid transport as lipoproteins. However, data on the ability of fatty acids to modulate gene expression in other tissues such as adipose tissue, endo-thelial cells, and macrophages are beginning to emerge in the literature. Although findings thus far have provided a valuable insight into the impact of dietary fat on the human genome, it is likely that it only represents the "tip of the iceberg." Given the vast body of evidence implicating dietary fat composition in the pathology of many chronic diseases including coronary heart disease (CHD), such nutrient-gene interaction information could provide us with valuable insights into how fatty acids changes can be used as a measure to reduce the public health burden of such diseases.

An understanding of the tissue specific metabolic effects of fatty acids relies on knowledge of the basic structure and nomenclature of fatty acids, of how they are absorbed and transported in the bloodstream, and upon reaching the target tissue are either stored, incorporated into the membrane bi-layer, or metabolized to active metabolites. Such information is detailed in the earlier part of the chapter.

The chapter, which is by no means exhaustive, will then proceed to examine some important fatty acid-gene interactions and their potential impact on cardiovascular health. For a more comprehensive examination of the area please refer to a number of excellent recently published review articles (1-5).

FATTY ACID STRUCTURE AND TISSUE SOURCES

All fatty acids have a common basic structure, consisting of a hydrocarbon chain and a terminal carboxyl group. About 21 are found in significant amounts in food and they are characterized according to the length of the hydrocarbon chain and the degree of saturation and the position of the double bonds, if present. The short (SCFA) and medium chain (MCFA) C2-C14 fatty acids are generally saturated in nature, whereas the C16-C22, long chain fatty acids (LCFA) may be saturated or unsaturated. The most abundant monounsaturated fatty acid is oleic acid, which is an 18 carbon fatty acid containing one double bond at carbon 9 from the methyl end, and is therefore depicted by the notation C18:1 n-9. Polyunsaturated fatty acids (PUFA), as the name suggests contain two or more double bonds, with the two major PUFA classes the n-3 and n-6 having the first double bond at C3 and C6, respectively. Alpha-linolenic (ALA, C18:3, n-3) and linoleic (LA, C18:2, n-6) acid are the precursors for the n-3 and n-6 fatty acid families, respectively, and are considered essential fatty acids as the mammalian body does not contain the enzymatic machinery to insert double bonds beyond the C9 position, therefore a dietary supply is necessary. The longer chain metabolic derivatives of these fatty acids eicosapentaenoic acid (EPA, C20:5, n-3) and arachidonic acid (AA, C20:4, n-6) often have opposing metabolic effects, in large part attributable to the fact that they give rise to different families of eicosanoid end products. The long chain n-3 PUFAs EPA, docosahexaenoic acid (DHA, C22:6, n-3) and doc-osapentaenoic acid (DPA, C22:5, n-3) are currently almost exclusively ingested as oily fish or fish oil capsules, although it is likely that genetic engineering will lead to a vegetable oil source within the next 10 years. Recent publications suggest that this series of LCFA may be the most significant fatty acid modulators of gene expression.

Tissues EPA and DHA may be synthesized from ALA through a series of elongation and desaturation reactions (Fig. 8.1). However, reaction efficiency is generally low (6), with an average estimated 7 M of ALA required to produce 1 M of EPA. Furthermore, as the n-6 fatty acid metabolic pathways uses the same desaturase enzymes, high dietary LA inhibits EPA formation (Fig. 8.1). In the UK current dietary intakes of 10.0 g LA per day compared with 1.6 g ALA (7) does not favor this metabolic conversion. Therefore, an increased consumption of fatty fish represents a more effective means of increasing total body content of LC n-3 PUFA. As currently fish is almost the exclusive dietary source, nonfish eaters must rely on conversion from the precursor ALA, which is naturally present in certain vegetable oils and green vegetables.

METABOLISM OF FATTY ACIDS Absorption

Fatty acids are ingested mainly in the form of triglycerides (TAG), which are hydrolyzed in the gut lumen under the action of lipases. The released fatty acids and monoacyl glycerol are taken up into the enterocyte, where the LCFA are re-esterified to form TAG. As fat is largely insoluble in the aqueous medium of the blood stream the TAG, cholesterol, and phospholipids are packaged into lipid-protein structures called chylomicrons, which contain apoB48

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