Tumor Necrosis Factor-Increased Hepatic Very-Low-Density Li pop rote in Production and Increased Serum Triglyceride Levels in Diabetic Rats KENNETH R. FEINGOLD, MOUNZER SOUED, SALEH ADI, ILONA STAPRANS, JUDY SHIGENAGA, WILLIAM DOERRLER, ARTHUR MOSER, AND CARL GRUNFELD Previous studies demonstrated that administration of tumor necrosis factor (TNF) to diabetic rats rapidly increases serum triglyceride levels and stimulates hepatic lipogenesis without affecting the activity of adipose tissue lipoprotein lipase or serum insulin levels. The purpose of this study was to determine the mechanism by which TNF increases serum triglyceride levels and stimulates hepatic fatty acid synthesis in diabetic animals. The maximal increase (-2-fold) in serum triglyceride levels in diabetic rats is seen with a dose of 10 ^g TNF/200 g body wt, and the half- maximal effect is observed with 5 |xg TNF/200 g body wt. The clearance of labeled triglyceride-rich lipoproteins from the circulation is not affected by TNF administration (triglyceride ty 2 : diabetic vs. TNF- administered diabetic, 3.5 ± 0.7 vs. 4.0 ± 0.6 min, respectively; NS). The production of triglyceride, measured by the Triton WR-1339 technique, is increased twofold in diabetic animals after TNF administration. These results indicate that the rapid increase in serum triglyceride levels after TNF treatment is accounted for by increased hepatic lipoprotein secretion. TNF administration did not alter either the amount or activation state of hepatic acetyl- CoA carboxylase, a key regulatory enzyme in fatty acid synthesis. There was also no change in the hepatic levels of fatty acyl-CoA, an allosteric inhibitor of acetyl-CoA carboxylase. However, there was a 71% increase in hepatic citrate concentrations. Citrate is an allosteric activator of acetyl-CoA carboxylase, and changes in hepatic citrate concentrations have been shown to mediate changes in the rates of fatty acid synthesis. These results suggest that the TNF-induced stimulation of hepatic lipogenesis is mediated by From the Department of Medicine, University of California, and the Metabolism Section and Lipid Research Laboratory, Medical Service, Veterans Admin- istration Medical Center, San Francisco, California. Address correspondence and reprint requests to Kenneth R. Feingold, MD, Metabolism Section (111F), VA Medical Center, 4150 Clement Street, San Francisco, CA 94121. Received for publication 2 February 1990 and accepted in revised form 6 August 1990. citrate activation of acetyl-CoA carboxylase. At 2 h after TNF administration, neither serum glucose nor p-hydroxybutyrate levels were adversely altered in the TNF group, indicating that the disturbances in lipid metabolism are not dependent on alterations in glycemic control. The increases in serum triglyceride levels that occur during infections or stress in diabetes may be secondary to TNF. Diabetes 39:1569- 74, 1990 I nfection in diabetic patients frequently results in various metabolic disturbances, including hyperglycemia, keto- sis, and hyperlipidemia (1,2). The response to infection involves many cell types and is mediated by cytokines (3-5). Recent experiments by our laboratory demonstrated that the administration of the cytokine tumor necrosis factor (TNF) to diabetic animals increased serum triglyceride levels 2.4-fold at 2 h and 4.3-fold at 17 h (6). Hepatic fatty acid synthesis, measured by the incorporation of tritiated water into fatty acids, was increased 45% at 1-2 h and 87% at 16-17 h after TNF administration (6). Under these condi- tions, TNF treatment did not affect serum insulin levels (6). As noted by others and as found in our experiments, adi- pose tissue lipoprotein lipase activity in diabetic animals is markedly suppressed (6-8). The administration of TNF to diabetic animals did not produce a further decrease in adi- pose lipoprotein lipase activity in the diabetic animals at either 2 or 17 h after TNF administration (6). These results indicate that the TNF-induced increase in serum lipid levels does not require changes in adipose tissue lipoprotein lipase activity. The purpose of this study was to determine the mechanism by which TNF acutely increases serum triglyceride levels in diabetic animals. Additionally, the mechanism by which TNF stimulates hepatic fatty acid synthesis was explored. RESEARCH DESIGN AND METHODS [ 14 C]cholesterol, [ 14 C]triolein, and [ 14 C]sodium bicarbonate were purchased from Du Pont-NEN (Boston, MA). Ready DIABETES, VOL. 39, DECEMBER 1990 1569