Hypertriglyceridemia Produced by Endotoxin: Role of Impaired Triglyceride Disposal Mechanisms

105

Chylomicrons have been shown to protect mice and rats against a lethal dose of lipopolysaccharide and may serve as a therapeutic means to protect against endotoxemia. However, the requisite of isolation from human lymph hampers pharmaceutical application. Recently, we developed recombinant chylomicrons from commercially available lipids and human recombinant apolipoprotein E. The current study explored the effectiveness of these apoE-enriched emulsions in redirecting LPS from Kupffer cells to liver parenchymal cells. Upon injection into rats, 125 I-LPS rapidly and specifically associated with the liver (64.3 Ϯ 3.1% of the injected dose) and spleen (4.1 Ϯ 0.7%). The uptake of LPS by the spleen was four-to fivefold reduced upon incubation with the apoE-enriched emulsion or free apoE ( P Ͻ 0.0001), but not with emulsion alone or Lipofundin. Within the liver, 125 I-LPS mainly associated with Kupffer cells. The uptake by Kupffer cells was eight-to ninefold reduced by the apoEenriched emulsion or apoE alone ( P Ͻ 0.01), and a 19.6-fold increased uptake ratio by liver parenchymal cells over Kupffer cells was observed. The emulsion without apoE had no effect on the in vivo kinetics of LPS. LPS interacted selectively with the apoE moiety of the recombinant chylomicron. Emulsion-associated and free apoE bound approximately two molecules of LPS, possibly by its exposed hydrophilic domain involving arginine residues. We anticipate that the protecting effect of endogenous chylomicrons against LPS-induced endotoxemia may result from the apoE moiety and that human recombinant apoE may serve as a therapeuticum to protect against endotoxemia. ( J. Clin. Invest. 1997. 99:2438-2445.)

Section: Introductionmentioning

confidence: 99%

Human recombinant apolipoprotein E redirects lipopolysaccharide from Kupffer cells to liver parenchymal cells in rats In vivo.

Rensen¹,

Oosten²,

Bilt³

et al. 1997

105

“…Hyperlipidemia, primarily due to the accumulation of VLDL, is one such metabolic aberration (2,3). Hyperlipidemia in models of infection has been observed in a wide variety of species including humans, monkeys, rabbits, dogs, and rats (2)(3)(4)(5)(6)(7)(8)(9)(10). Studies have shown that model infections result in both a decrease in the metabolism ofcirculating lipoproteins (8,9) and an increase in hepatic lipid synthesis (10).…”

Section: Introductionmentioning

confidence: 99%

Effect of tumor necrosis factor (TNF) on lipid metabolism in the diabetic rat. Evidence that inhibition of adipose tissue lipoprotein lipase activity is not required for TNF-induced hyperlipidemia.

Feingold¹,

Soued²,

Staprãns³

et al. 1989

119

“…Key words: lipoproteins * triglycerides * lipopolysaccharide * cytokines * liver mediate the acute phase response, a change in the hepatic synthetic program with increased production of acute phase proteins that aid host defense (4)(5)(6)(7). The host response to infection also includes cytokine-mediated changes in intermediary metabolism such as hypertriglyceridemia (8,9), which is due to both increases in hepatic triglyceride-rich lipoprotein synthesis (10,11 ) and decreases in lipoprotein lipase-mediated lipoprotein clearance ( 12,13).…”

mentioning

confidence: 99%

Chylomicrons alter the fate of endotoxin, decreasing tumor necrosis factor release and preventing death.

Harris

Grünfeld²,

Feingold³

et al. 1993

197

179

The hypertriglyceridemia of infection was traditionally thought to represent the mobilization of substrate to fuel the body's response to the infectious challenge. However, we have previously shown that triglyceride-rich lipoproteins can protect against endotoxin-induced lethality. The current studies examine the mechanism by which this protection occurs. Rats infused with a lethal dose of endotoxin preincubated with chylomicrons had a reduced mortality compared with rats infused with endotoxin alone (15 vs. 76%, P < 0.001). Preincubation with chylomicrons increased the rate of clearance of endotoxin from plasma and doubled the amount of endotoxin cleared by the liver (30±1 vs. 14±2% of the total infused radiolabel, P < 0.001). In addition, autoradiographic studies showed that chylomicrons directed more of the endotoxin to hepatocytes and away from hepatic macrophages. Rats infused with endotoxin plus chylomicrons also showed reduced peak serum levels of tumor necrosis factor as compared with controls (14.2±3.3 vs. 44.9±9.5 ng/ml, mean±SEM, P = 0.014). In separate experiments, chylomicrons (1,000 mg triglyceride/kg) or saline were infused 10 min before the infusion of endotoxin. Chylomicron pretreatment resulted in a reduced mortality compared with rats infused with endotoxin alone (22 vs. 78%, P < 0.005). Therefore, chylomicrons can protect against endotoxin-induced lethality with and without preincubation with endotoxin. The mechanism by which chylomicrons protect against endotoxin appears to involve the shunting of endotoxin to hepatocytes and away from macrophages, thereby decreasing macrophage activation and the secretion of cytokines. (J. Clin. Invest. 1993. 91:1028-1034.) Key words: lipoproteins * triglycerides * lipopolysaccharide * cytokines * liver mediate the acute phase response, a change in the hepatic synthetic program with increased production of acute phase proteins that aid host defense (4-7). The host response to infection also includes cytokine-mediated changes in intermediary metabolism such as hypertriglyceridemia (8,9), which is due to both increases in hepatic triglyceride-rich lipoprotein synthesis (10, 11 ) and decreases in lipoprotein lipase-mediated lipoprotein clearance ( 12, 13).The increased production of triglyceride-rich lipoproteins by the liver is now postulated to be a part of the acute phase response, as lipoproteins serve not only as a potential source of metabolic fuel ( 14) but also as direct participants in the protective process. All lipoproteins, including cholesterol-rich HDL (15)(16)(17)(18)(19)(20) and and triglyceride-rich VLDL and chylomicrons ( 19,20), have been shown to bind endotoxin, subsequently reducing its toxic properties. Recent data from our laboratory has demonstrated a dose-dependent increase in mouse survival when varying concentrations of either VLDL or chylomicrons were incubated with a lethal dose of Escherichia coli endotoxin before its intraperitoneal injection (20). In addition, we found that in normal humans triglyceride-rich lipoprotei...