Accumulating evidence supports the notion that systemic and cellular metabolism profoundly affects the functions of immune cells. Whether lifelong hypolipidemia impacts immune cell proportions and functions is completely unknown. Familial Combined Hypolipidemia (FHBL2) is a rare genetic disorder characterised by very low levels of plasmatic lipoproteins and caused by mutations in the angiopoietin-like 3 (ANGPTL3) gene, encoding for a protein that inhibits extracellular lipases. FHBL2 condition is not associated with an increased risk of immune-mediated diseases and thus represents a unique platform to test the immunoprotective effects of hypolipidemia. Here we propose to investigate immune functions in FHBL2 subjects through an unbiased transcriptomic analysis of peripheral blood mononuclear cells. To this aim, RNA will be extracted and RNA-Seq will be performed in cells obtained from 4 FHBL2 and age- and sex-matched healthy controls, and results will be analysed in order to reveal which immune cell subsets may be represented at different frequencies, and which immune and non-immune pathways may be altered, in FHBL2 subjects compared to controls. This proposal stems from the collaboration between two groups with complementary expertise in immunology and in lipid metabolism, and is expected to generate novel information about immune-metabolic crosstalk which may have important implications for understanding and treating dyslipidemias and metabolic syndrome.
The links between hyperlipidemia and immune activation have been already established. Conversely, the effects of lifelong hypolipidemia on immune cells are completely unknown. FHBL2 subjects represent a unique opportunity to investigate this phenomenon. If the results confirm our hypothesis, that hypolipidemia promote immune tolerance, our study could provide new information on the involvement of the immune system into the protective effects of hypolipidemic regimens or therapies. The omic approach and the unbiased analysis that we propose to use will generate a large amount of new data on immune and non-immune pathways that are possibly regulated by ANGPTL3 in immune cells. Indeed, we expect that our analysis will reveal novel immune-cell intrinsic metabolic pathways that are affected by systemic hypolipidemia and that may impact their immune functions. For instance, regulatory T cells, known to control unwanted inflammation including metabolic inflammation, need to synthesize cholesterol to optimally proliferate (Zeng et al. 2013): it is conceivable that, in FHBL2 subjects, decreased cholesterol availability may reduce their uptake of exogenous cholesterol and in turn promote their endogenous biosynthesis and proliferation. In line with these data, exogenous cholesterol supplementation suppresses the genes of the mevalonate pathway in Tregs (Timilshina et al. 2019). In turn, Treg reduction has been reported in response to chronic hypercholesterolemia (Maganto-Garcia et al. 2011). Another example of the possible outcome of the study may be the identification of a role in immune cells for ß-hydroxybutyrate, a ketone body that is consistently high in these subjects (Tikkanen et al. 2019): interestingly, this metabolite is a potent inhibitor of inflammasome activation (Youm et al. 2015). We envisage that the results of our exploratory study may identify which mechanisms will be worth investigating thanks to future collaborative efforts.
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