Endothelial mechanotransduction, metabolism and lipoprotein transport in atherosclerosis: Jan Borén, Gothenburg, Sweden
Atherosclerosis: metabolism dysfunction drives inflammation in the vessels
Jan Borén is Professor and Chair of the Department of Molecular and Clinical Medicine at the Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Director of the Sahlgrenska Center for Molecular and Clinical Medicine, and physician at the Department of Clinical Chemistry, Sahlgrenska University Hospital. After obtaining his MD at the University of Gothenburg, and his PhD at the Department of Medical Biochemistry, University of Gothenburg, he undertook a research fellowship and was Staff Research Investigator at Gladstone Institute of Cardiovascular Disease, University of California San Francisco, USA (1994-1998). His main long-term research interest focuses on understanding the underlying mechanisms that lead to, and consequences of, lipid accumulation in the liver, arterial wall and heart, with the goal of translating this knowledge into effective treatment.
There is incontrovertible evidence that low-density lipoprotein cholesterol (LDL-C) is causal for atherosclerotic cardiovascular disease (ASCVD). Movement of LDL across the endothelium and its accumulation in the arterial wall are the initial steps in atherogenesis. Previously, this was thought to be a passive process initiated by entry at a site of compromised endothelial barrier. Recent insights, however, have overturned this concept. Studies showed that LDL transcytosis across the endothelium is an active process, dependent on the function of caveolae, scavenger receptor B1 (SR-B1), activin receptor-like kinase 1 (ALK1), and LDL receptor (LDLR), whereas high-density lipoproteins (HDL) and its major protein component apolipoprotein AI transcytose endothelial cells through SR-B1, and the ATP-Binding cassette transporters A1 and G1.
Furthermore, these lipoprotein receptors also participate in signal transduction to modulate cellular functions to either accelerate or block atherogenesis. While in vitro approaches have identified key players in signal transduction pathways, further study is needed to elaborate signalling pathways by which lipoprotein receptors influence atherogenesis in vivo. Improved understanding of these mechanisms and signalling pathways may offer new therapeutic potential for targeting the early events of atherosclerosis.
Borén J, Packard CJ, Taskinen MR. The roles of ApoC-III on the metabolism of triglyceride-rich lipoproteins in humans. Front Endocrinol (Lausanne). 2020;11:474.
Borén J, Chapman MJ, Krauss RM, Packard CJ, Bentzon JF, Binder CJ, Daemen MJ, Demer LL, Hegele RA, Nicholls SJ, Nordestgaard BG, Watts GF, Bruckert E, Fazio S, Ference BA, Graham I, Horton JD, Landmesser U, Laufs U, Masana L, Pasterkamp G, Raal FJ, Ray KK, Schunkert H, Taskinen MR, van de Sluis B, Wiklund O, Tokgozoglu L, Catapano AL, Ginsberg HN. Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2020;41:2313-2330.
Björnson E, Packard CJ, Adiels M, Andersson L, Matikainen N, Söderlund S, Kahri J, Hakkarainen A, Lundbom N, Lundbom J, Sihlbom C, Thorsell A, Zhou H, Taskinen MR, Borén J. Apolipoprotein B48 metabolism in chylomicrons and very low-density lipoproteins and its role in triglyceride transport in normo- and hypertriglyceridemic human subjects. J Intern Med 2020;288:422-438.