Triglyceride-Rich Lipoproteins and Remnants: Targets for Therapy?

Abstract

It is now evident that elevated circulating levels of triglycerides in the non-fasting state, a marker for triglyceride (TG)-rich remnant particles, are associated with increased risk of premature cardiovascular disease (CVD). Recent findings from basic and clinical studies have begun to elucidate the mechanisms that contribute to the atherogenicity of these apoB-containing particles. Here, we review current knowledge of the formation, intravascular remodelling and catabolism of TG-rich lipoproteins and highlight (i) the pivotal players involved in this process, including lipoprotein lipase, glycosylphosphatidylinositol HDL binding protein 1 (GPIHBP1), apolipoprotein (apo) C-II, apoC-III, angiopoietin-like protein (ANGPTL) 3, 4 and 8, apoA-V and cholesteryl ester transfer protein; (ii) key determinants of triglyceride (TG) levels and notably rates of production of very-low-density lipoprotein 1 (VLDL1) particles; and (iii) the mechanisms which underlie the atherogenicity of remnant particles. Finally, we emphasise the polygenic nature of moderate hypertriglyceridemia and briefly discuss modalities for its clinical management. Several new therapeutic strategies to attenuate hypertriglyceridemia have appeared recently, among which those targeted to apoC-III appear to hold considerable promise.

Keywords: Apolipoprotein; Heparin sulphate proteoglycan; Triglycerides.

Fig. 1

LPL is synthesised in parenchymal cells in muscle and adipose tissue and then transported to the endothelial cell surface. LPL-mediated TG lipolysis at this surface is the first essential step in TG homeostasis. TGs are hydrolysed by LPL bound to GPIHBP1 in a process that is dependent on apoC-II. ApoC-III and apoA-V are potential inhibitors of LPL-mediated lipolysis. Upon TG hydrolysis, free fatty acids are taken up by surrounding tissues

Fig. 2

Transcytosis enable the influx of lipoproteins over the vessel wall. This process is mediated by clathrin. The average diameter of these transport vesicles are around 100 nm, which only allows transport of lipoproteins with the size of 70 nm or smaller, thereby excluding chylomicrons and large VLDL remnant particles. The average transport speed is around 2500 vesicles per minute. The retention of lipoproteins in the subendothelial space is mediated by the interaction between positively charged residues on apoB and apoE and the negatively charged sulphate groups in the glycosaminoglycans chains of HSPG expressed on the vessel wall