Regulation of the plasma non-esterified fatty acid concentration in the postprandial state.

NEFA, also known as free fatty acids (FFA), are the form in which stored body fat is transported from adipose tissue to its sites of utilization (Fig. 1). Their importance was recognized in the 1950s once methods became available for their reliable measurement in plasma. Because of the rapid turnover of plasma NEFA, they constitute a large proportion of the ‘energy flux’ through the bloodstream, particularly in the post-absorptive and fasting states when their contribution relative to glucose increases. Thus, NEFA transport through the plasma is an essential part of normal life, and regulation of the plasma NEFA concentration is part of the normal pattern of metabolic regulation during feeding and fasting. However, it has been appreciated since the work of Randle et al. (1963) that inappropriately elevated plasma NEFA concentrations could have adverse metabolic effects (Table 1). NEFA will compete with glucose for utilization by insulin-sensitive peripheral tissues (myocardium and skeletal muscle), leading to impaired glucose utilization. NEFA will stimulate hepatic glucose production, further impairing glucose tolerance. There is evidence from studies with isolated hepatocytes that NEFA may reduce hepatocyte insulin binding (Svedberg et al. 1990), thus reducing the normal large extraction of insulin which occurs on its first passage through the liver. The resulting systemic hyperinsulinaemia will lead ultimately to down-regulation of insulin-mediated processes, and hence insulin resistance. On the lipid side, the supply of NEFA to the liver is a major determinant of the rate of hepatic VLDL-triacylglycerol (TAG) secretion (Kissebah et al. 1976; Byrne et al. 1991). Increased NEFA supply, therefore, may lead to elevated VLDL-TAG secretion and hence hypertriacylglycerolaemia. There are wellestablished links between insulin resistance and other adverse conditions such as hypertension, and between insulin resistance, hypertriacylglycerolaemia and an atherogenic lipoprotein profile including a preponderance of small, dense LDL particles and a decreased HDL-cholesterol concentration (DeFronzo & Ferrannini, 199 1 ; Frayn, 1993). Therefore, inappropriately elevated NEFA concentrations may be seen as central to the insulin resistance syndrome (Frayn et al. 19966). In addition, the well-recognized link between fat ingestion and activation of the coagulation cascade may reflect changes in plasma NEFA concentration (Mitropoulos et al. 1994; Silveira et al. 1994), although that area is outside the scope of the present review. However, this is a simplistic black and white view of a substrate which is highly variable in concentration both from place-to-place within the circulation, and from minuteto-minute during the normal day (Fig. 2). The role of NEFA might be defined more clearly by asking: where and when are elevated NEFA concentrations ‘inappropriate’ or ‘adverse’? The answer to ‘where?’ is clear: many of the adverse effects discussed previously are mediated in the liver, and an increased supply of NEFA in the portal vein is likely to have