Tumor Necrosis Factor Acutely Increases Plasma Levels of Very Low Density Lipoproteins of Normal Size and Composition*

Abstract

Tumor necrosis factor (TNF) has been proposed to mediate the hypertriglyceridemic response to infection by either increasing hepatic lipid synthesis or decreasing clearance of triglyceride-rich particles through inhibition of lipoprotein lipase. We demonstrate that within 90 min of administration of recombinant human TNF alpha to rats there is a rapid increase in plasma levels of very low density lipoproteins (VLDL) of normal ultracentrifugal flotation rate, apoprotein and lipid composition, and particle size, as assessed by nondenaturing gradient gel electrophoresis. Clearance of radioiodinated VLDL 90 min after TNF administration did not differ from that in control animals, consistent with other observations that increases in plasma triglyceride concentrations after TNF precede detectable reductions in tissue lipoprotein lipase activity. Between 90 min and 16 h after TNF, VLDL levels decline, and there are increases in intermediate (IDL) and low (LDL) density lipoproteins consistent with lipolytic processing of VLDL, although the findings are also compatible with direct secretion of IDL and LDL subspecies. By 16 h, there is a 50% increase in protein mass of LDL of normal composition and subspecies distribution, as assessed by nondenaturing gradient gel electrophoresis. These data suggest that the initial locus of TNF's metabolic effects is the liver, and the resulting increases in secretion and metabolic processing of VLDL may represent an early manifestation of the acute phase response.