Obese patients have lower sepsis
mortality termed the “obesity
paradox.” We hypothesized that lipopolysaccharide, known to be carried within lipoproteins such as very low density lipoprotein, could be sequestered in adipose tissue
; potentially contributing a survival benefit.
University research laboratory.
Subjects and Patients: Vldlr
knockout mice to decrease very low density lipoprotein receptors, Pcsk9
knockout mice to increase very low density lipoprotein receptor
, and Ldlr
knockout mice to decrease low density lipoprotein receptors. Differentiated 3T3-L1 adipocytes. Caucasian septic shock patients.
We measured lipopolysaccharide uptake into adipose tissue
6 hours after injection of fluorescent lipopolysaccharide into mice. Lipopolysaccharide uptake and very low density lipoprotein receptor
protein expression were measured in adipocytes. To determine relevance to humans, we genotyped the VLDLR
rs7852409 G/C single-nucleotide polymorphism
in 519 patients and examined the association of 28-day survival with genotype.
Measurements and Main Results:
Lipopolysaccharide injected into mice was found in adipose tissue
within 6 hours and was dependent on very low density lipoprotein receptor
but not low density lipoprotein receptors. In an adipocyte cell line decreased very low density lipoprotein receptor
expression resulted in decreased lipopolysaccharide uptake. In septic shock patients, the minor C allele of VLDLR
rs7852409 was associated with increased survival (p
= 0.010). Previously published data indicate that the C allele is a gain-of-function variant of VLDLR
which may increase sequestration of very low density lipoprotein (and lipopolysaccharide within very low density lipoprotein) into adipose tissue
. When body mass index less than 25 this survival effect was accentuated and when body mass index greater than or equal to 25 this effect was diminished suggesting that the effect of variation in very low density lipoprotein receptor
function is overwhelmed when copious adipose tissue
Lipopolysaccharide may be sequestered in adipose tissue
via the very low density lipoprotein receptor
and this sequestration may contribute to improved sepsis