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129 ClinicalScience (1981) 61,129-133 EDITORIAL REVIEW Regulation of hepatic triacylglycerol synthesis and lipoprotein metabolism by glucocorticoids D . N. B R I N D L E Y Department of Biochemistry, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, UX. The excessive synthesis and storage of triacylglycerol (triglyceride) has a number of clinical implications. It is obviously the main symptom of obesity where excess lipid is stored in adipose tissue. Abnormal accumulations of triacylglycerols can also be manifested as a fatty liver, e.g. as a'result of the ingestion or inhalation of toxic compounds and damage to the liver. These conditions are often associated with an increase in the rate of triacylglycerol synthesis in the liver and are aggravated if the ability to secrete the triacylglycerol in very-low-density lipoproteins (VLDL) is impaired. If the increased synthesis of triacylglycerol results in a greater secretion of VLDL, then this implies that the flux of cholesterol into low-density lipoprotein (LDL) should also be increased. This is because cholesterol is secreted as part of the VLDL particle to facilitate the transport of triacylglycerol. When the triacylglycerol is removed from the VLDL by the action of lipoprotein lipase (EC 3.1.1.34), the cholesterol appears in the circulation in lowdensity lipoproteins. It therefore seems important to understand how the body controls triacylglycerol metabolism and to identify the mechanisms by which the synthesis of triacylglycerols in the liver becomes raised. At present this knowledge is incomplete, but it has become evident from animal work that the availability of glucocorticoids is an important factor 11, 21. Although the control of glucocorticoid metabolism in experimental animals is probably different from that in man, nevertheless their effects on metabolism are likely to be Key words: atherosclerosis, diabetes, diet, ethanol, fatty liver, fructose, glucocorticoids, insulin, lipid metabolism, lipoprotein lipase, lipoproteins, obesity, L-a-phosphatidate phosphohydrolase, sorbitol, stress, 'triglycerides. Abbreviations: LDL, low-density lipoproteins; VLDL, very-low-density lipoproteins. 9 similar. High concentrations of circulating cortisol are associated with excessive fat deposition in Cushing's syndrome and in obesity in experimental animals 131. Most human obesity is not associated with gross elevations of serum cortisol concentrations, but obesity may involve an increased sensitivity to glucocorticoid action [31. These hormones facilitate the action of insulin in stimulating the synthesis of fatty acids [4,5]. Their effects on the synthesis of triacylglycerols in liver seem to be more direct and the available evidence indicates that they stimulate the synthesis of the enzyme phosphatidate phosphohydrolase [ 1, 21. The 'microsomal and soluble phosphatidate phosphohydrolase (Fig. 1) have a regulatory function, particularly in enabling the liver to synthesize increased quantities of triacylglycerol. This enzymic adaptation therefore partly explains why injections of corticotropin or glucocorticoids stimulate hepatic triacylglycerol synthesis [2, 61 and produce a fatty liver [7, 81 Glucocorticoids also promote the secretion of VLDL [9, 101. The influence of glucocorticoids on the activity of phosphatidate phosphohydrolase is particularly apparent in stress conditions. This activity can increase in starvation [ l 1, 121, mildly ketotic diabetes [ 131, severely ketotic diabetes [ 141, hypoxia [ 151, after surgical stress including subtotal hepatectomy [ 121, and after hydrazine injection [16, 171. It may seem paradoxical that the capacity of the liver to synthesize triacylglycerols should increase in conditions where the concentrations of circulating glucagon, catecholamines and glucocorticoids increase relative to insulin. The liver receives a large supply of fatty acids from adipose tissue and decreases its own synthesis of these acids. The latter event is accompanied by a decreased concentration of malonyl-coenzyme A (CoA), a key intermediate in this process, which also inhibits Poxidation 0143-S221/81/OS0129-OS$Ol.S0/1 @ 1981 The Biochemical Society and the Medical Research Society D. N.Brindley 130 ADIPOSE TISSUE LIVER VLDL VLDL Ketones J + Pdhway increased ---+Pathway decreased FIG. 1. Fatty acid metabolism in severe ketotic diabetes or severe stress. The direction of fatty acid metabolism in severe diabetes or stress where the concentration of insulin to glucagon, catecholamines, corticotropin and glucocorticoids is very low is shown. The enzyme activities that are referred to are indicated by: (1) glycerophosphate acyltransferase (EC 2.3.1.15); (2) carnitine palmitoyltransferase (EC 2.3.1.21); (3) phosphatidate L-a-phosphohydrolase (EC 3.1.3.4); (4) lipoprotein lipase (EC 3.1.1.34). [ 181 through its action on carnitine palmitoyltransferase. Lack of insulin has also been reported to decrease the activity of glycerophosphate acyltransferase, particularly that in the mitochondria1 fraction [ 191. These changes promote the partitioning of fatty acids into poxidation and ketogenesis rather than into esterification (Fig. 1). However, the supply of fatty acids to the liver often exceeds its need for energy production via ,&oxidation, and the excess acids and their acyl-CoA esters are potentially toxic. Their conversion into triacylglycerols enables them to be stored temporarily in a safe form and allows CoA to be regenerated. This explains why these stress conditions are often accompanied by a fatty liver. The liver can also secrete this triacylglycerol provided that lipoprotein synthesis is not inhibited as it may be in some toxic conditions. This VLDL secretion can increase in ketotic diabetes [20] and, since insulin is required for the activity of lipoprotein lipase in adipose tissue, triacylglycerol clearance is decreased and a hypertriglyceridaemia results (Fig. 1). The action of insulin in increasing lipoprotein lipase activity in adipose tissue can be potentiated by gluco- corticoids [2 11. By contrast, the lipoprotein lipase activity in heart appears to be maintained primarily by glucocorticoids and insulin may promote this action [22]. This ability of the heart to oxidize and esterify fatty acids is also high in keototic diabetes 1231. In this condition the liver is supplying energy to the heart in the form of triacylglycerols and ketones, and to the brain as glucose and ketones. In this instance the control of hepatic phosphatidate phosphohydrolase by glucocorticoids appears to resemble their control of some enzymes of gluconeogenesis. The diurnal peak of corticosterone in rats occurs about 4 h before the maximum food intake 1241. This peak is probably responsible for the increased synthesis of phosphatidate phosphohydrolase, so that its activity is greatest when the liver increases its synthesis of fatty acids. Nutrients such as glycerol, sorbitol, fructose and ethanol stimulate hepatic triacylglycerol synthesis. When these are given as acute loads to rats, they provoke a much larger glucocorticoid response than does the equivalent load of glucose and they do not increase insulin concentrations [251. The effect of the former nutrients again increases phosphatidate phosphohydrolase ac- Glucocorticoids and lipid metabolism tivity a few hours later [261. This stimulation by ethanol and the accompanying increase in the synthesis and accumulation of triacylglycerols in the liver can be largely prevented if the rats are adrenalectomized and then given sodium chloride solution (150 mmol/l) to drink [25]. Alternatively, chronic administration of the hypolipidaemic drug, benfluorex, also diminishes the ethanolinduced increase in corticosterone, the increase in phosphohydrolase activity and the stimulation of triacylglycerol synthesis [27,281. When rats were fed diets enriched with fat, the duration of the corticosterone response to feeding the fructose load was prolonged (111; D. N. Brindley, J. Cooling, H. P. Glenny, S. L. Burditt & I. S. McKechnie, unpublished work). This may partly explain why high-fat diets exaggerate the effects of sucrose 129, 301, sorbitol 1311 and ethanol [32-341 in stimulating hepatic triacylglycerol synthesis and in promoting a hypertriglyceridaemia. It has also been reported that feeding high-fat diets to rats increases their stress reactions to cold [351, and the production of corticosterone in response to Nembutal narcosis and to corticotropin injection [36]. This increased sensitivity to stress, and the high glucocorticoid concentrations that can result, could contribute to the hyperglycaemia and insulin resistance that has been observed in rats fed a high proportion of dietary fat L37-411. This condition is likely to be accompanied by a decreased number of insulinbinding sites on adipocytes and hepatocytes 142, 431. A decreased number of insulin-binding sites is also seen in the hepatocytes of rats with a pituitary tumour that secretes somatotropin, prolactin and corticotropin and this is accompanied by insulin resistance [441. Rats fed high-fat rather than high-carbohydrate diets have high lipoprotein lipase activities in their cardiac and skeletal muscles, whereas the activity in adipose tissue is low ([451; N. Lawson & D. N. Brindley, unpublished work). This alteration can also be understood in terms of the greater production of corticosteroids and the insulin insensitivity that can accompany fat feeding. The discussion so far has been concerned with the effects of glucocorticoids on triacylglycerol and lipoprotein metabolism particularly in relation to the effects of insulin. Glucocorticoids stimulate triacylglycerol synthesis, VLDL secretion and therefore the flux of cholesterol into LDL. They may also aggravate insulin insensitivity. These actions could contribute to their observed effects in producing hypertriglyceridaemia and hypercholesterolaemia [46-481. Glucocorticoid concentrations in the blood are likely to be high in stress, diabetes, after smoking 131 [49-5 11 and after consuming diets rich in sucrose b21, fat 11, 361 and low in ascorbate [53-551. Furthermore there are likely to be interactions amongst these conditions. High concentrations of glucocorticoids have been reported to cause damage to vascular endothelial cells and to the intima [56, 571, to retard cell growth 1581, to decrease platelet and whole-blood clotting times [59, 601 and they can induce hypertension [611. There also appears to be a close correlation between moderate and severe atherosclerosis in human beings and high concentrations of circulating glucocorticoids [621. Taken together these observations provide one possible link between many of the acknowledged risk factors associated with an increased incidence of atherosclerosis and changes in hormonal balance. This article has attempted to review how increases in the availability of glucocorticoids could modify the direction and rate of triacylglycerol synthesis and lipoprotein metabolism. It is hoped that this information may contribute to a better understanding of the biochemical changes that occur in complex metabolic diseases such as fatty liver, obesity, diabetes and atherosclerosis. Conclusions Glucocorticoids increase the activity and concentration of L-cc-phosphatidate phosphohydrolase (EC 3.1.3.4) in the liver. This enzyme has an important regulatory function and this change facilitates the increased synthesis, accumulation and secretion of triacylglycerols by the liver. The increased production of very-low-density lipoprotein also means that the ultimate flux of cholesterol into low-density lipoproteins is increased. If insulin concentrations are low, or if there is insulin insensitivity, then the clearance of circulating triacylglycerol by adipose tissue decreases and a hypertriglyceridaemia may result. The clearance of triacylglycerols by the heart can increase in relative terms, since its lipoprotein lipase activity is maintained by glucocorticoids rather than by insulin. Changes in glucocorticoid status may be significant in determining the effects on metabolism of stress, diabetes, smoking and the consumption of diets deficient in ascorbate or rich in sucrose, sorbitol, ethanol and fat. It is proposed that changes in glucocorticoid status that could occur in these conditions could contribute to the development of fatty livers, 132 D.N . Brindley maturity onset diabetes, obesity and atherosclerosis. 1201 NIKKILA, E.A. & KEKKI, M. 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