Endotoxin rapidly induces changes in lipid metabolism that produce hypertriglyceridemia: low doses stimulate hepatic triglyceride production while high doses inhibit clearance

Endotoxin rapidly induces changes in lipid
metabolism that produce hypertriglyceridemia: low
doses stimulate hepatic triglyceride production
while high doses inhibit clearance

Kenneth R. Feingold, Ilona Staprans, Riaz A. Memon, Arthur H. Moser, Judy K.
Shigenaga, William Doerrler, Charles A. Dinarello, and Carl Grunfeld'
Department of Medicine, University of California, San Francisco; Metabolism Section, Medical Service,
and Lipid Research Laboratory, Department of Veterans Affairs Medical Center, San Francisco, CA; and
Tufts University, New England Medical Center, Boston, MA
Abstract

Hyperlipidemia frequently accompanies infectious
diseases and may be due to increases in lipoprotein production
or decreases in lipoprotein clearance. The administration of endotoxin
(LPS) has been used to mimic infection and prior
studies demonstrate that LPS produces hypertriglyceridemia. In
the present study in rodents, the dose of LPS necessary to induce
hyperlipidemia was orders of magnitude less than that necessary
to induce shock and death. As little as 10 ng/100 g body weight
induced hypertriglyceridemia and this increase in serum
triglyceride levels occurred rapidly (78% increase at 2 h). At
high doses of LPS (50 pg/lOO g body weight), the clearance of
triglyceride-rich lipoproteins was decreased. At low doses of LPS
(100 ng/100 g body weight), triglyceride clearance was not altered
but the hepatic secretion of triglyceride was increased. Low
dose LPS stimulated hepatic de novo fatty acid synthesis and
lipolysis, both of which provided a source of fatty acids for the
increase in hepatic triglyceride production. High dose LPS did
not increase hepatic fatty acid synthesis or peripheral lipolysis,
and hepatic triglyceride secretion was not stimulated. Thus, low
dose LPS produces hypertriglyceridemia by increasing hepatic
lipoprotein production, while high dose LPS produces hypertriglyceridemia
by decreasing lipoprotein catabolism. Administration
of anti-tumor necrosis factor (TNF) antibodies or interleukin
1 (IL-1) receptor antagonist did not prevent the increase
in serum triglyceride levels induced by LPS. However, anti-TNF
antibodies and interleukin 1 receptor antagonist (IL-lra)
blocked the increase in serum triglycerides induced by TNF or
IL-1, respectively. These data suggest that neither of these
cytokines is absolutely required for the increase in serum
triglycerides induced by LPS, raising the possibility that other
cytokines, small molecular mediators, or LPS itself may play a
crucial role.-Feingold, K. R., I. Staprans, R. A. Memon, A. H.
Moser, J. K. Shigenaga, W. Doerrler, C. A. Dinarello, and C.
Grunfeld. Endotoxin rapidly induces changes in lipid
metabolism that produce hypertriglyceridemia: low doses stimulate
hepatic triglyceride production while high doses inhibit
clearance. J Lipid Res. 1992. 33: 1765-1776.