New York, USA
Alan Tall MB BS is the Tilden-Weger-Bieler Professor of Medicine and head of the Division of Molecular Medicine in the Department of Medicine of Columbia University. Dr. Tall is internationally recognized for his work on plasma lipoproteins and atherosclerosis. Dr. Tall discovered mutations in the cholesteryl ester transfer protein (CETP) gene that are associated with dramatically increased HDL levels and reduced LDL levels, establishing the role of CETP in the regulation of human lipoproteins and identifying CETP as a potential therapeutic target.
Dr. Tall has done research on the ATP binding cassette transporters ABCA1 and ABCG1 that promote cholesterol efflux from macrophage foam cells to apoA-1 and HDL particles, respectively. This work has also identified a key role of cholesterol efflux pathways in regulating the proliferation of hematopoietic stem and progenitor cells and the production of pro-atherogenic myeloid cells and platelets. Recently the Tall laboratory has focused efforts on understanding the mechanisms underlying the association of human GWAS variants with plasma lipoproteins and coronary heart disease. This has led to an elucidation of the role of a scaffolding protein TTC39B in the ubiquitination and turnover of LXR, with impact on HDL levels, steato-hepatitis and atherosclerosis. In recognition of his work, Dr Tall was the recipient of the Irvine Page Award, the Robert I. Levy Lectureship and the Distinguished Scientist Award of the American Heart Association.
Sun 23 Apr
Anitschkow Lecture: Hematopoiesis, cholesterol and atherosclerosis
Dr. Tall is internationally recognized for his work on plasma lipoproteins and atherosclerosis. His contributions include:
- Discovery of mutations in the cholesteryl ester transfer protein (CETP) gene that are associated with dramatically increased levels of high density lipoprotein (HDL) and reduced levels of low-density lipoprotein (LDL), thus establishing the role of CETP in the regulation of human lipoproteins and identifying CETP as a potential therapeutic target
- Research on the ATP binding cassette transporters ABCA1 and ABCG1 that promote cholesterol efflux from macrophage foam cells to apolipoprotein A-1 and HDL particles
- esearch on the ATP binding cassette transporters ABCA1 and ABCG1 that promote cholesterol efflux from macrophage foam cells to apolipoprotein A-1 and HDL particles
- Identification of the key role of cholesterol efflux pathways in the regulation of the proliferation of haematopoietic stem and progenitor cells and the production of pro-atherogenic myeloid cells and platelets.
- Elucidation of the role of a scaffolding protein TTC39B in the ubiquitination and turnover of liver receptor (LXR), with impact on HDL levels, steatohepatitis and atherosclerosis.
In his Anitschkow Lecture, Professor Tall will discuss recent findings linking haematopoiesis, cholesterol and atherosclerosis.
Hypercholesterolaemia is well established as a major modifiable risk factor for atherothrombotic disease. Moreover, there is also evidence that plasma cholesterol levels modulate haematopoiesis by influencing platelet biogenesis and activation. Activated platelets form aggregates with neutrophils and monocytes, and the resulting cross talk between platelets and leukocytes influences inﬂammatory cytokine production, leukotriene biosynthesis, as well as production of reactive oxygen species. Prolonged exposure to elevated plasma cholesterol levels can also promote overproduction of monocytes by haematopoietic stem and multipotential progenitor cells, precursors of macrophages, resulting in monocytosis. In addition, accumulation of cholesterol may disturb plasma membrane structures and thus affect the signaling of cell surface receptors. All of these effects would contribute to atherothrombosis.
While human genome-wide association studies have revealed novel genetic loci involving platelet and leukocyte production that are associated with coronary heart disease, elucidation of the underlying mechanisms that explain the cross-talk between haematopoiesis, cholesterol and atherothrombosis is still at an early stage. There is, however, some evidence to suggest a role for mechanisms that influence haematopoietic cellular cholesterol efflux, notably those involving the ABC transporters and apolipoproteins. For example, experimental studies point to the involvement of ABCG4, a transporter that is highly homologous to ABCG1, which promotes cholesterol efﬂux to high-density lipoproteins (HDL). Thus, as well as conventional approaches to preventing atherothrombosis, such as the use of treatments to lower plasma low-density lipoprotein levels and anti-platelet drugs, therapies targeting abnormal haematopoiesis may have potential in the future.
Wang W, Tang Y, Wang Y, Tascau L, Balcerek J, Tong W, Levine RL, Welch C, Tall AR, Wang N. LNK/SH2B3 Loss of Function promotes atherosclerosis and thrombosis. Circ Res 2016;119:e91-e103.
Murphy AJ, Tall AR. Disordered haematopoiesis and athero-thrombosis. Eur Heart J 2016;37:1113-21.
Wang N, Tall AR. Cholesterol in platelet biogenesis and activation. Blood 2016;127:1949-53.