LAUSR

Accumulating evidence points to the causal role of triglyceride-rich lipoproteins and their cholesterol-enriched remnants in atherogenesis. Genetic studies in particular have not only revealed a relationship between plasma triglyceride levels and the risk of atherosclerotic cardiovascular disease, but have also identified key proteins responsible for the regulation of triglyceride transport. Kinetic studies in humans using stable isotope tracers have been especially useful in delineating the function of these proteins and revealing the hitherto unappreciated complexity of triglyceride-rich lipoprotein metabolism. Given that triglyceride is an essential energy source for mammals, triglyceride transport is regulated by numerous mechanisms that balance availability with the energy demands of the body. Ongoing investigations are focused on determining the consequences of dysregulation as a result of either dietary imprudence or genetic variation that increases the risk of atherosclerosis and pancreatitis. The identification of molecular control mechanisms involved in triglyceride metabolism has laid the groundwork for a ‘precision-medicine’ approach to therapy. Novel pharmacological agents under development have specific molecular targets within a regulatory framework, and their deployment heralds a new era in lipid-lowering-mediated prevention of disease. In this Review, we outline what is known about the dysregulation of triglyceride transport in human hypertriglyceridaemia. In this Review, Borén and colleagues provide an overview of the pathways involved in triglyceride-rich lipoprotein (TRL) assembly and intravascular processing, and discuss how the dysregulation of triglyceride transport can result in hypertriglyceridaemia. Triglyceride-rich lipoproteins (TRLs), in particular, their cholesterol-rich remnants, are now considered causal agents for atherogenesis and a suitable target for diet-based and drug-based interventions to prevent coronary heart disease. The optimal level of plasma triglycerides is <1.2 mmol/l; plasma triglyceride levels >1.2 mmol/l are associated with increasing risk of atherosclerosis and pancreatitis (the latter in particular when plasma triglyceride levels are >10 mmol/l). Highly regulated metabolic pathways control the release of TRLs in their tissues of origin (the intestine and liver), lipolysis and remodeling in the bloodstream, and clearance of remnant particles after the core triglycerides have been delivered to their destination is normally rapid and is facilitated by hepatic receptors. Given that current treatments are inadequate in reducing triglycerides to optimal levels, novel treatments under development focus on increasing the efficiency of lipolysis and finding an approach to regulate plasma levels of TRLs and their remnants. Large-scale outcome trials will be required to test the hypothesis that specifically lowering TRLs and remnants can reduce the risk of cardiovascular disease. Triglyceride-rich lipoproteins (TRLs), in particular, their cholesterol-rich remnants, are now considered causal agents for atherogenesis and a suitable target for diet-based and drug-based interventions to prevent coronary heart disease. The optimal level of plasma triglycerides is <1.2 mmol/l; plasma triglyceride levels >1.2 mmol/l are associated with increasing risk of atherosclerosis and pancreatitis (the latter in particular when plasma triglyceride levels are >10 mmol/l). Highly regulated metabolic pathways control the release of TRLs in their tissues of origin (the intestine and liver), lipolysis and remodeling in the bloodstream, and clearance of remnant particles after the core triglycerides have been delivered to their destination is normally rapid and is facilitated by hepatic receptors. Given that current treatments are inadequate in reducing triglycerides to optimal levels, novel treatments under development focus on increasing the efficiency of lipolysis and finding an approach to regulate plasma levels of TRLs and their remnants. Large-scale outcome trials will be required to test the hypothesis that specifically lowering TRLs and remnants can reduce the risk of cardiovascular disease.