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Very Low Density Lipoprotein Receptor Sequesters Lipopolysaccharide Into Adipose Tissue During Sepsis

Shimada, Tadanaga MD, PhD1; Topchiy, Elena PhD1; Leung, Alex K. K. PhD1; Kong, HyeJin J. BSc1; Genga, Kelly R. MD1; Boyd, John H. MD1; Russell, James A. MD1; Oda, Shigeto MD, PhD2; Nakada, Taka-aki MD, PhD2; Hirasawa, Hiroyuki MD, PhD2; Walley, Keith R. MD1

doi: 10.1097/CCM.0000000000004064
Clinical Investigation: PDF Only
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Objectives: 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 during sepsis; potentially contributing a survival benefit.

Design: Retrospective analysis.

Setting: 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.

Interventions: 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 is present.

Conclusions: Lipopolysaccharide may be sequestered in adipose tissue via the very low density lipoprotein receptor and this sequestration may contribute to improved sepsis survival.

1Centre for Heart Lung Innovation, St. Paul’s Hospital, University of British Columbia, Vancouver, BC, Canada.

2Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.

Drs. Shimada, Topchiy, and Leung, Ms. Kong, and Dr. Nakada performed the experiments. Drs. Shimada, Topchiy, and Leung, Ms. Kong, and Drs. Genga, Oda, Nakada, and Hirasawa analyzed the data. Drs. Shimada and Walley wrote the article. The guarantors are Drs. Shimada and Walley. All authors reviewed the results and approved final version of the article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Dr. Russell received funding from Asahi Kasei Pharmaceuticals of America, La Jolla Pharmaceuticals (he chaired the Data Safety and Monitoring Board of a trial of angiotensin II from 2015 to 2017), Ferring Pharmaceuticals, Cubist Pharmaceuticals, Leading Biosciences (share options), Grifols (investigator-initiated grant to his institution), and CytoVale. Dr. Russell reports patents owned by the University of British Columbia (UBC) that are related to proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor(s) and sepsis and related to the use of vasopressin in septic shock; he is an inventor on these patents. Dr. Russell is a founder, Director, and shareholder in Cyon Therapeutics, and he is a shareholder in Molecular You Corp. Dr. Walley disclosed that he is supported by an operating grant (FDN 154311) from the Canadian Institutes of Health Research and an inventor on a patent filed by the UBC related to PCSK9 in sepsis. The remaining authors have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: Keith.Walley@hli.ubc.ca

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