The adipocyte, fatty acid trapping, and atherogenesis.

Abstract

Much effort has been spent to identify the factors that contribute to coronary artery disease. Not surprisingly, adipose tissue has gained little attention to date in this search because no immediate and critical links between adipocyte metabolism and atherogenesis may be evident to most people. But coronary artery disease is a public health problem only in societies with high fatty acid intakes; therefore, our purpose is to outline a hypothesis that adipose tissue dysfunction may be a very common—indeed, perhaps even the most common— cause of the dyslipoproteinemia and insulin resistance that so frequently lead to coronary disease. This complex and multifaceted syndrome has received many names, depending on the original point of interest. Amongst these names are hyperapoB, 1 familial combined hyperlipidemia, 2 syndrome X, 3 the plurimetabolic syndrome, 4 the visceral fat syndrome, 5 familial dyslipidemic hypertension, 6 the atherogenic lipoprotein phenotype, 7 and the deadly quartet. 8 Whether these titles are different names for the same disorder or different disorders with similar features is not clear; but it is the pathophysiology of their common features on which we will concentrate. Among the most important of these features are increased numbers of the smaller, denser LDL particles, postprandial hyperlipemia, hypertriglyceridemia, low HDL cholesterol, high fasting and postprandial fatty acid levels, and insulin resistance. Until now, excess release of fatty acids from adipocytes caused by increased lipolysis 9 has been the only mechanism suggested to link adipocyte dysfunction and dyslipidemia. In our opinion, although excess lipolysis may be of importance in certain situations, it is not likely to be the sole link between adipose tissue dysfunction and atherosclerosis. The hypothesis that will be outlined herein differs substantially from the current views and is based on the metabolic insights that have been gained from the recent recognition of the ASP pathway. 10 Along with insulin, ASP is a principal determinant of the rate of triglyceride synthesis in adipocytes 11 and therefore is a principal determinant of the rate of fatty acid uptake or, as we shall describe it herein, fatty acid trapping by adipocytes. In brief, we postulate that failure to trap the normal proportion of dietary fatty acids in adipocytes leads to their abnormal diversion to liver and muscle, and from this abnormal diversion stems the complex array of metabolic alterations listed above that so markedly increase the risk of vascular disease in these patients.