Professor Chris Packard: Triglyceride metabolism and its clinical implications
Chris Packard is the R&D Director of NHS Greater Glasgow & Clyde, Scotland. He holds an Honorary Professorship of Vascular Biochemistry at the University of Glasgow, and is a Consultant Clinical Scientist for NHS Greater Glasgow & Clyde Biochemistry. Over his career, Professor Packard has focussed on two aspects of atherosclerosis research, lipoprotein metabolism and how it is affected by diets and drugs, and large-scale clinical trials of lipid lowering agents. More recently his interest has widened to include investigations of emerging risk factors for coronary heart disease (CHD) and the consequences of social deprivation for health. Key contributions include evaluation of the role of the LDL receptor in vivo, the discovery of metabolic channelling in the apolipoprotein B lipoprotein delipidation cascade, and the formulation of models to explain the generation of small, dense LDL. More recent research has focussed on the metabolic consequences of insulin resistance, the causes of the dyslipidaemia in metabolic syndrome, and exploration of the mechanism of action of novel lipid lowering drugs. Professor Packard is principal investigator of the ongoing pSoBid study, an epidemiological study of the psychosocial and biological determinants of ill health and premature CHD in deprived communities in the east end of Glasgow. He was founding chairman of NEXXUS, the West of Scotland Bioscience Network which promoted community building and knowledge exchange between life sciences industry, academia and the NHS.
While low-density lipoprotein cholesterol (LDL-C) is established as causal for atherosclerotic cardiovascular disease (ASCVD) and the primary lipid target for therapeutic intervention, it is recognised that even at very low LDL-C levels, patients continue to experience cardiovascular events. With the increasing prevalence of elevated triglycerides (TG) among populations, a consequence of escalating obesity and cardiometabolic disease, there has been renewed interest in the role of TG-rich lipoproteins in ASCVD. Indeed, there is supportive evidence from general population studies demonstrating a strong, positive association between plasma TG levels and risk of ASCVD, as well as studies of genetic variants involved in regulating TG metabolism that are associated with differences in ASCVD outcomes.
Together, these findings have driven further study of the metabolism of TG-rich lipoproteins, which is complex and intertwined with that of cholesterol metabolism. As plasma TG levels increase, there is accumulation of large, TG-rich very low-density lipoproteins (VLDL), specifically VLDL1. These enter a delipidation cascade resulting in the formation of smaller TG-rich lipoproteins and eventually LDL. There is, however, metabolic heterogeneity within this delipidation pathway. Genetic insights have proved integral to understanding the factors that regulate TG-rich lipoprotein metabolism and identifying novel targets for therapeutic intervention.
Unlike LDL-C, however, deciphering the relationship between the decrease in plasma TG and reduction in ASCVD, is challenging given the complexity of TG-rich metabolism. Future investigation has important implications for the development of novel therapeutic approaches to TG-lowering in high-risk patients with well-controlled LDL-C levels.
Vallejo-Vaz AJ, Packard CJ, Ference BA, Santos RD, Kastelein JJP, Stein EA, Catapano AL, Pedersen TR, Watts GF, Ray KK. LDL-cholesterol lowering and clinical outcomes in hypercholesterolemic subjects with and without a familial hypercholesterolemia phenotype: Analysis from the secondary prevention 4S trial. Atherosclerosis 2021; 320:1-9.
Taskinen MR, Björnson E, Kahri J, Söderlund S, Matikainen N, Porthan K, Ainola M, Hakkarainen A, Lundbom N, Fermanelli V, Fuchs J, Thorsell A, Kronenberg F, Andersson L, Adiels M, Packard CJ, Borén J. Effects of evolocumab on the postprandial kinetics of apo (apolipoprotein) B100- and B48-containing lipoproteins in subjects with type 2 diabetes. Arterioscler Thromb Vasc Biol 2020: ATVBAHA120315446.
Katzmann JL, Packard CJ, Chapman MJ, Katzmann I, Laufs U. Targeting RNA With Antisense Oligonucleotides and Small Interfering RNA: JACC State-of-the-Art Review. J Am Coll Cardiol 2020;76:563-579.
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.