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Dyslipidemia, Inflammation and Atherosclerosis in Metabolic Diseases

Principal investigator :
Philippe Lesnik, Ph.D.

Research team :

Anatol Kontush, Maryse Guérin, Thierry Huby, Wilfried Le Goff, Alain Carrié, Philippe Couvert, Philippe Giral, Jean-Marc Lacorte, Eric Bruckert, Xavier Girerd, Emmanuel Gautier, Isabelle Guillas, Tiphaine Le Roy and Emelyne Lecuyer.

[See all of Dr. Lesnik’s videos here]

The underlying pathogenesis of atherosclerosis involves an imbalance of lipid metabolism and a maladaptive immune response entailing a chronic inflammation of the arterial wall. During the last years, we have developed tools and performed translational proof-of-concept studies in animals and humans to clarify cellular and molecular mechanisms of such lipido-inflammatory and immune responses. We propose to extend these studies around three main axes: (i) to determine how a crosstalk between lipids and immune cells influences atherogenesis, (ii) to assess the clinical relevance of novel mechanisms, genes, and biomarkers discovered as above, and (iii) to evaluate new therapeutic approaches to treat inflammatory metabolic disorders and to delay atherogenesis. Novel molecular mechanisms, translational developments and clinical strategies targeting lipid-related inflammation are studied in the framework of four complementary working themes. Our major focus are on innate and adaptive immune responses, reverse cholesterol transport, HDL function, as well as on other cardiometabolic risk factors (postprandial hypertriglyceridemia, diabetes, obesity, autoimmune responses) potentially affecting stabilization and regression of atherosclerotic plaques. This research builds on our extensive methodological expertise in the field of cardiovascular diseases notably in lipidomics and flow cytometry. The themes of our research programme are as follows: (I) Cellular lipids and immuno-inflammation: dissecting molecular & cellular pathways; (II) Epigenetics and genetics of dyslipidemia: identification of new genes and regulatory mechanisms; (III) HDL lipidomics, structure and function: decoding determinants and biomarkers of HDL dysfunctionality; (IV) Post- prandial state and lipoprotein metabolism: deciphering glucido-lipido- and inflammatory postprandial responses.

FOCUS

Our research goals are based on the premise that lipid-related inflammation and the associated immune responses are dominant components in atherogenesis.


BIOSKETCH

Philippe Lesnik obtained his Ph.D. in Molecular and Cellular Biology at the University of Pierre and Marie Curie in 1993. From 1999-2002 he was a Visiting Investigator at the Gladstone Institute of Cardiovascular Disease, University of California. He was head of the INSERM U939 “Dyslipidemias, Inflammation and Atherosclerosis in Metabolic Diseases” which merged with 5 other teams in 2014 forming a large research entity (INSERM U1166) working on CardioMetabolic Diseases. He currently leads the research team “Integrative Biology of Atherosclerosis”. Dr. Lesnik has a strong background in lipoprotein metabolism and atherosclerosis, as well as developing mouse models to dissect in vivo the physiopathological mechanisms that contribute to the progression or regression of the disease. Dr. Lesnik places particular emphasis on the role of cellular players of the innate and adaptive immunity, cellular regulatory networks influenced by environmental and metabolic changes and key cellular lipid sensors/receptors. He developed transgenic mouse strains enriched or depleted in mononuclear cells to explore the relationships between the immune system and atherosclerosis. He has discovered a strong inverse relationship between dendritic cell populations and plasma cholesterol levels. The hypothesis is that dendritic cells actively participate in the control of gut microbiota composition, therefore selecting specific bacterial communities, which can differentially affect steroid transformation (cholesterol, faecal sterols and primary and secondary biliary acids). Such bacterial species may consequently influence dietary cholesterol availability and the absorption of sterols from the enterohepatic cycle and thus have effects on cholesterol excretion. In this context, Dr. Lesnik addresses cholesterol metabolism by the gut microbiota and its consequences on cholesterolemia and atherosclerosis development.


Publications

Elevated CETP activity improves plasma cholesterol efflux capacity from human macrophages in women. Villard EF, El Khoury P, Duchene E, Bonnefont-Rousselot D, Clement K, Bruckert E, Bittar R, Le Goff W, Guerin M. Arterioscler Thromb Vasc Biol. 2012 Oct;32(10):2341-9.

Small, dense high-density lipoprotein-3 particles are enriched in negatively charged phospholipids: relevance to cellular cholesterol efflux, antioxidative, antithrombotic, anti-inflammatory, and antiapoptotic functionalities. Camont L, Lhomme M, Rached F, Le Goff W, Nègre-Salvayre A, Salvayre R, Calzada C, Lagarde M, Chapman MJ, Kontush A. Arterioscler Thromb Vasc Biol. 2013 Dec;33(12):2715-23.

Local apoptosis mediates clearance of macrophages from resolving inflammation in mice. Gautier EL, Ivanov S, Lesnik P, Randolph GJ. Blood. 2013 Oct 10;122(15):2714-22.

Adrenocortical scavenger receptor class B type I deficiency exacerbates endotoxic shock and precipitates sepsis-induced mortality in mice. Gilibert S, Galle-Treger L, Moreau M, Saint-Charles F, Costa S, Ballaire R, Couvert P, Carrié A, Lesnik P, Huby T. J Immunol. 2014 Jul 15;193(2):817-26.

Adipocyte ATP-binding cassette G1 promotes triglyceride storage, fat mass growth, and human obesity. Frisdal E, Le Lay S, Hooton H, Poupel L, Olivier M, Alili R, Plengpanich W, Villard EF, Gilibert S, Lhomme M, Superville A, Miftah-Alkhair L, Chapman MJ, Dallinga-Thie GM, Venteclef N, Poitou C, Tordjman J, Lesnik P, Kontush A, Huby T, Dugail I, Clement K, Guerin M, Le Goff W. Diabetes. 2015 Mar;64(3):840-55.

Promoting macrophage survival delays progression of pre-existing atherosclerotic lesions through macrophage-derived apoE. Bouchareychas L, Pirault J, Saint-Charles F, Deswaerte V, Le Roy T, Jessup W, Giral P, Le Goff W, Huby T, Gautier EL, Lesnik P. Cardiovascular Res. 2015 in press.