Chylomicrons enhance endotoxin excretion in

Chylomicrons prevent endotoxin toxicity and increase endotoxin uptake by hepatocytes. As a consequence, less endotoxin is available to activate macrophages, thereby reducing tumor necrosis factor secretion. To determine whether the chylomicron-mediated increase in hepatocellular uptake of endotoxin results in increased endotoxin excretion into bile, we examined bile after endotoxin administration. A sublethal dose (7 pg/kg) of 1251-endotoxin was incubated with either rat mesenteric lymph containing nascent chylomicrons (500 mg of chylomicron triglyceride per kg of body weight) or an equal volume of normal saline (controls) for 3 h and then infused into male Sprague-Dawley rats. Bile samples were collected via a common bile duct catheter for 24 h. Infusion of endotoxin incubated with chylomicrons increased biliary excretion of endotoxin by 67% at 3 h (P 5 0.006) and by 20% at 24 h (P c 0.01) compared with infusion of endotoxin incubated in saline. Endotoxin activity, as measured by the Limulus assay, was not detected in the bile of test animals. However, endotoxin activity was detected after hot phenol-water extraction of bile, demonstrating that endotoxin is inactive in the presence of bile but retains bioactivity after hepatic processing. Since the majority of an intravenous endotoxin load has been shown to be cleared by the liver, acceleration of hepatocyte clearance and biliary excretion of endotoxin may represent a component of the mechanism by which chylomicrons protect against endotoxin-induced lethality. Endotoxemia stimulates changes in lipid metabolism, including an increase in plasma triglyceride (TG) (1, 13, 19, 26, 57). It has been proposed that the hypertriglyceridemia observed during gram-negative sepsis represents the mobilization of fat stores to fuel the body's metabolic response to the infectious challenge (3, 7, 30). However, there is data to suggest that TG-rich lipoproteins are components of the acute-phase response. One of the earliest and most consistent metabolic responses to endotoxin is an increase in plasma TG levels due to an increase in TG-rich very-low-density lipoprotein (VLDL) (13). This endotoxin-stimulated hypertriglyceridemia may have a protective function, since TG-rich lipoproteins (VLDL and chylomicrons) have been shown to bind endotoxin and inhibit its activity (11, 20, 21, 53). We have demonstrated that chylomicrons and VLDL, when incubated with lethal doses of endotoxin prior to intraperitoneal administration, inhibit detection of endotoxin by the Limulus assay in vitro (11, 20) and protect mice from death (21). Chylomicrons also prevent death in rats when given intravenously prior to a dose of endotoxin (22). In …