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Metabolism of triglyceride-rich lipoproteins in health and dyslipidaemia

Abstract

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.

Key points

  • 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.

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Fig. 1: Regulatory pathways involved in the assembly and secretion of triglyceride-rich lipoproteins.
Fig. 2: Biosynthesis and secretion of VLDL from the liver.
Fig. 3: Regulation of lipolysis and clearance of TRLs.
Fig. 4: Simulation depicting the typical patterns of postprandial accumulation of apoB-100 and apoB-48 across 24 h.
Fig. 5: Role of TRLs and their remnants in atherogenesis.

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Acknowledgements

The authors acknowledge funding from the Swedish Research Council, the Swedish Heart–Lung Foundation, the Swedish state under the agreement between the Swedish government and the county councils (ALFGBG-965404; J.B.), and the Finnish Foundation of Cardiovascular Research (M.-R.T.). The authors thank R. Perkins (University of Gothenburg, Sweden) for help with editing this manuscript.

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J.B., M.-R.T. and C.J.P. researched data for this manuscript. All the authors contributed to the discussion of its content and wrote, reviewed and edited the manuscript before submission.

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Correspondence to Jan Borén.

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Nature Reviews Cardiology thanks David Cohen, who co-reviewed with Michele Alves-Bezerra; Daniel Rader; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Borén, J., Taskinen, MR., Björnson, E. et al. Metabolism of triglyceride-rich lipoproteins in health and dyslipidaemia. Nat Rev Cardiol 19, 577–592 (2022). https://doi.org/10.1038/s41569-022-00676-y

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