Background: Bacterial endotoxins (LPS) elicit dramatic responses in the host, including elevated plasma lipid levels due to increased synthesis and secretion of triglyceride (TG)-rich lipoproteins by the liver and inhibition of lipoprotein lipase. This cytokine-induced hyperlipoproteinemia, clinically termed the "lipemia of sepsis," was customarily thought to involve the mobilization of lipid stores to fuel the host response to infection. However, since lipoproteins can also bind and neutralize LPS, our lab has long postulated that TG-rich lipoproteins (very low density lipoproteins and chylomicrons) are also components of an innate, non-adaptive host immune response to infection. Our research to date has demonstrated the capacity of lipoproteins to bind LPS, protect against LPS-induced toxicity, and modulate the overall host response to this bacterial toxin. In addition, we have described a process in which the internalization of lipoprotein-bound LPS by hepatocytes induces in these hepatic epithelial cells an attenuated responsiveness to pro-inflammatory cytokines. Consequently, we hypothesize that TG-rich lipoproteins, in addition to their established role transporting dietary lipid, combine with pathogenic lipid antigens to exert an immunomodulatory effect on the liver and other tissues critical to the host immune response to infection and acute injury. What regulates this process, especially the molecular mechanisms underlying the induction of “cytokine tolerance,” is currently unknown and of central importance. Ultimately a better understanding of how TG-rich lipoproteins modulate the body’s response to LPS could yield novel biological insights with important clinical implications.
Major goals: (i) examine the molecular mechanisms governing lipoprotein-pathogenic lipid interactions and how these complexes impact host immunity; (ii) delineate the neuroendocrine signals which regulate both lipid metabolism and the host acute inflammtory response.
Active Research Lipoprotein-bound endotoxin as an immunomodulator: Triglyceride-rich lipoproteins, e.g. chylomicrons (CM), can bind the lipid domain of several pathogenic bacterial lipid antigens, including LPS and lipotechoic acid. Further, once bound the lipids are neutralized, cleared more rapidly from the circulation, and predominantly deposited within hepatic epithelial cells via interactions with the LDL receptor. We are currently studying how CM-LPS complexes induce a state of relative cytokine tolerance in hepatocytes and other cells critical to the body’s response to infection, including vascular endothelial cells and circulating mononuclear cells. These studies use both in vivo rodent models of sepsis and in vitro cell culture systems to determine how CM-LPS complexes modulate pathogen-induced immune responses.
Apolipoprotein E and hepatic antigen presentation: Apolipoprotein (apo) E is now recognized as a pleiotropic molecule important in several biological processes and human disease states. In addition to its well-described role in lipoprotein metabolism and cardiovascular disease, this 34.2-kd glycoprotein has been linked to Alzheimer’s disease, dementia, diabetes, breast cancer, multiple sclerosis, stroke, kidney disease and the immune response to infection. Recent data has further implicated apo E as playing an important role in CD1d-mediated lipid antigen presentation to NKT cells. We are engaged in a series of studies using molecular, biochemical and immunological strategies to determine how this intriguing process takes place in the liver.
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Biomedical Sciences (BMS) Graduate Program
