We have previously shown that administration of tumor necrosis factor-alpha (TNF alpha) to intact rats results in an acute (within 60-120 min) stimulation of hepatic fatty acid synthesis, which persists for an extended period. Hepatic cholesterol synthesis is also stimulated by 16-17 h after TNF alpha treatment. We now demonstrate, using intact mice, that stimulation of hepatic lipid synthesis is not solely the property of the cytokine TNF alpha. Incorporation of 3H2O into fatty acids in the liver was increased 60-120 min and 16-17 h after the administration of TNF beta, interleukin-1 (IL-1), and interferon-alpha (IFN alpha). TNF alpha, IL-1, and IFN alpha all rapidly stimulate hepatic fatty acid synthesis (within 0-30 min), with the peak occurring at 60-120 min. The half-maximal doses of TNF alpha (200 ng) and IL-1 (20 ng) that stimulate hepatic fatty acid synthesis are similar to those that induce fever, a well recognized biological effect of these cytokines. Additionally, hepatic cholesterol synthesis was increased 16-17 h after TNF beta, IL-1, and IFN gamma treatment. The present study demonstrates that multiple cytokines from different cell types which act through different receptors can stimulate hepatic fatty acid and cholesterol synthesis. Previous studies have shown that multiple cytokines can inhibit the synthesis and storage of fat in cultured adipose cells. Taken together, these data indicate that multiple signals to perturb lipid metabolism may be produced as a consequence of an immunological or inflammatory response.

Tumor necrosis factor (TNF) administration produces an increase in plasma triglycerides that may be due to inhibition of adipose lipoprotein lipase activity and/or a stimulation of hepatic ipogenesis. We now report that TNF administration to insulinopenic diabetic rats increases serum triglycerides (2 h

Infection and inflammation are associated with hypertriglyceridemia, which is thought to be mediated by cytokines. Previous studies at our laboratory and others have shown that tumor necrosis factor acutely increases serum triglyceride levels primarily by stimulating hepatic lipid synthesis and secretion. The role of interleukin-1 (IL-1), a cytokine that is also secreted by stimulated macrophages and that has many actions that overlap those of tumor necrosis factor, has not been studied in depth. The present study demonstrates that IL-1, at doses similar to those that cause fever and anorexia and that stimulate adrenocorticotropic hormone secretion, rapidly increases serum triglyceride levels; this elevation persists for at least 17 hours. Serum cholesterol levels are not altered by IL-1. Neither is the clearance of triglyceride-rich lipoproteins affected by IL-1. However, hepatic triglyceride secretion, measured by the Triton WR-1339 technique, is increased in IL-1-treated animals. Accompanying this stimulation in hepatic lipid secretion is an increase in de novo fatty acid synthesis in the liver. IL-1 does not increase serum free fatty acid and glycerol levels, suggesting that IL-1 does not stimulate lipolysis in vivo. Additionally, inhibition of lipolysis does not prevent the increase in serum triglyceride levels, providing further evidence that lipolysis does not play a crucial role in the increased hepatic lipid synthesis and secretion induced by IL-1. In contrast, tumor necrosis factor increases lipolysis, which contributes to the increase in serum trigtycerides. That multiple cytokines rapidly elevate plasma triglyceride levels suggest that these changes in lipid metabolism may play an important role in the organism's response to infection and inflammation. (Arteriosclerosis and Thrombosis 1991;ll:495-500)

Tumor necrosis factor (TNF) increases serum triglycerides in rats by increasing de novo hepatic fatty acid synthesis and very low density lipoprotein production. We have recently shown that several other cytokines increase hepatic fatty acid synthesis in the mouse. We now explore the mechanism by which these cytokines increase de novo lipogenesis and the interactions between cytokines in fed mice. TNF administration results in increased hepatic levels of citrate, the primary allosteric activator of acetyl-CoA carboxylase, which is the major rate-limiting enzyme for fatty acid synthesis. The TNF-induced increase in citrate occurs within 15 min of administration, early enough to account for the acute rise in hepatic fatty acid synthesis seen by 30 min after TNF administration. IL-1, which also increases hepatic fatty acid synthesis, produces similar increases in hepatic citrate levels. In contrast, another potent stimulator of hepatic fatty acid synthesis, interferon-alpha (IFN alpha), has no effect on hepatic citrate levels. There were no acute effects of TNF or IL-1 on the activation state of acetyl-CoA carboxylase. A trend toward an increase in the activation state of acetyl-CoA carboxylase was seen after IFN alpha administration. Low doses of TNF and IL-1 given in combination show no synergy while maximal doses are not additive. In contrast, when a low dose of either TNF or IL-1 is combined with a low dose of IFN alpha, there is synergy in stimulating hepatic fatty acid synthesis. A maximal dose of TNF or IL-1 and a high dose of IFN alpha produce a further increase in hepatic fatty acid synthesis. These data support the concept that there are two classes of cytokines that stimulate hepatic fatty acid synthesis, those that can increase hepatic citrate levels and those that cannot.