Effects of adrenalectomy and dexamethasone on hepatic lipid metabolism'

The influence of adrenalectomy and dexamethasone on hepatic free fatty acid metabolism was studied in isolated perfused livers from male rats. Adrenalectomy 1 week prior to perfusion did not affect uptake of oleate, output of triglyceride, or rate of ketogenesis compared to sham-operated match-fed controls. Livers from dexamethasone-treated rats (0-2 mg/kg per day for 7 days) removed less oleate from the perfusate, esterified more to total and very low density lipoprotein (VLDL) triglyceride, and oxidized less to ketone bodies, compared to match fed controls; additional studies with [ 1 -'4C]oleate confirmed these findings. The output of glucose by livers from dexamethasone-treated rats was also stimulated. The output of VLDL triglyceride was correlated with output of total perfusate triglyceride ( r = 0.77, P < 0.001). Prior to perfusion, dexamethasone livers accumulated more triglyceride than did control livers. Adrenalectomy did not affect the concentration of plasma free fatty acid or blood ketones and glucose; however, the plasma concentration of triglyceride was elevated. Dexamethasone increased the concentration of plasma free fatty acid, total triglyceride, and VLDL protein, triglyceride, phospholipid, and free cholesterol. No changes were observed in the concentration or composition of plasma low density lipoprotein (LDL) lipids. The concentration of plasma high density lipoprotein (HDL) protein and lipid, and plasma apoA-I, tended to increase; the ratio of total H D L cholesterol to LDL cholesterol was elevated with dexamethasone treatment. These observations suggest that augmented synthesis and secretion of VLDL triglyceride contribute to glucocorticoid-induced hypertrig1yceridemia.-Cole, T. G., H. G. Wilcox, and M. Heimberg. Effects of adrenalectomy and dexamethasone on hepatic lipid metabolism. J . Lipid Res. 1982. 23 81-91. Supplementary key words VLDL LDL H D L lipoprotein lipase Adrenal glucocorticoids can induce hypertriglyceridemia in experimental animals and man (3-6). Since, in the postabsorptive state, the liver is the primary source of plasma triglycerides secreted in the form of the very low density lipoprotein (VLDL), effects of glucocoticoids on hepatic production and secretion of the VLDL may contribute to the induced hypertriglyceridemia. In addition, hypertriglyceridemia may result from reduced peripheral clearance, and/or reduced activity of lipoprotein lipase (7). The results of previous investigations from this laboratory suggested that the synthesis and secretion of triglyceride by the perfused rat liver were stimulated following administration of cortisone to the animal (8, Columbia, M O 65212 9). Increased hepatic secretion of triglyceride has also been reported in the rat and mouse (10, 1 1 ) and increased numbers of VLDL-like particles are associated with the hepatic Golgi apparatus following glucocorticoid administration (10, 12, 13). Bagdade et al. (11) investigated the secretion of triglyceride by the liver in vivo and the activity of adipose tissue lipoprotein lipase (LPL) in rats treated with dexamethasone (DEX) under conditions of constant weight gain; they concluded that, although both processes contributed to the hypertriglyceridemia, the reduced utilization of triglyceride due to depressed LPL activity was the more important factor. To clarify further the effects of adrenal glucocorticoids on hepatic metabolism of free fatty acid (FFA) and on the possible hepatic role in hypertriglyceridemia, the present study was undertaken. For these experiments, the metabolism of FFA by isolated perfused livers from adrenalectomized rats and from rats treated with various amounts of DEX was examined. In addition, the effects of DEX on the lipids and apolipoproteins of the plasma lipoproteins were determined. Preliminary reports of this work have been presented (1 , 2).