Role of insulin in hepatic fatty acid partitioning: emerging concepts.

The effects of insulin action on hepatic lipid metabolism are increasingly emerging as central factors in the integration of the metabolic status of the whole animal. In humans, insulin resistance results in derangements of liver metabolism which are associated with such clinically important conditions as obesity, diabetes and atherosclerosis. The perceived role of the liver in the aetiology of these conditions has attracted extensive research in the area, and several reviews have appeared in recent years that deal with aspects of the role of the hormone in the control of liver lipid metabolism (see, e.g., [1–3]). The aim of the present one is not to duplicate these, but rather to suggest possible ways in which newly acquired information can be combined with other well-established phenomena in the formulation of an integrated theory of control of the hepatic partitioning of fatty acid metabolism by insulin. The approach adopted is purposely speculative, in the anticipation that this is most likely to stimulate novel ideas and work. The liver plays a central role in orchestrating the delivery of substrates to peripheral tissues. In the process, it partly determines the circulating concentrations of metabolites and lipoproteins. The traffic is bidirectional and, under any particular set of physiological conditions, a balance is established as a result of the rates of secretion by the liver, uptake by peripheral tissues and re-uptake by the liver. This is perhaps best exemplified by lipid substrates, because the liver plays such a central role in the metabolismof fatty acids and cholesterol. Both canbe synthesized by the liver, and are also delivered to it in the circulation. Fatty acids are esterified to produce triacylglycerols (TAGs) and phospholipids which, together with unesterified cholesterol and cholesteryl esters, make up the lipid components of very-lowdensity lipoproteins (VLDL) secreted by the liver. Their secretion, combined with the ability of the peripheral tissues to metabolize them and of the liver itself to clear the remnants or products of the metabolism of VLDL (and chylomicrons secreted from the gut), determines the levels of such important parameters as the plasma concentrations of triacylglycerol, esterified and unesterified cholesterol and of the remnants themselves. Hepatic fatty acid and cholesterol metabolism is therefore intimately linked, and insulin plays an important role in determining the outcome of their metabolism within the liver. Insulin affects hepatic lipid metabolism directly through its actions to modulate the expression of enzymes or secretory proteins [e.g. apolipoprotein B (apoB); see below], and indirectly by determining the rate of delivery of esterified or non-esterified fatty acids to the liver, through its antilipolytic effect on adipose tissue and its influence on the expression of lipoprotein lipase activity. Much of the interest in the effects of insulin has centred on the role of the liver in the aetiology of non-insulin-dependent diabetes mellitus and its associated insulin resistance. In this respect, it has become increasingly appreciated that a deficient