Causes and Consequences of Hypertriglyceridemia

Figures

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  Figure 1. Apolipoprotein B 100 metabolic heterogeneity in hypertriglyceridemia. Elevation in plasma triglyceride is associated with an increased concentration of large VLDL-VLDL1 (A). VLDL1 once secreted from the liver enters a delipidation cascade leading to the formation of smaller VLDL2, IDL, and LDL (main diagram). Kinetic investigations reveal metabolic heterogeneity within the delipidation pathway. As shown in (B) [taken from Björnson et al. (29)], a tracer of deuterated leucine administered at time 0 h appears rapidly in VLDL1 and VLDL2. Decay curves in both fractions have an initial rapid phase reflecting lipolysis and a second, slower phase due to remnant removal. This metabolic heterogeneity (as depicted by the two circles in each lipoprotein class in the main diagram) is more evident as plasma triglyceride rises (B). For further detail see Packard and Shepherd (13), Björnson et al. (29), Shepherd and Packard (30), and Packard et al. (31).

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  Figure 2. Apolipoprotein B100 metabolic cascade in hypertriglyceridemia. Plasma triglyceride levels influence the metabolism of LDL as an extension of the metabolic heterogeneity seen in Figure 1. LDL is derived from the delipidation of VLDL1 but the extent of conversion is less than for VLDL2. The LDL (followed by virtue of the radioactive label attached to VLDL1 apoB) from VLDL1 has a slow catabolic rate (A). LDL derived from VLDL2 delipidation exhibits a two-phase clearance curve. The first part represents LDL with a rapid clearance rate (presumably derived from directly secreted VLDL2) while the second phase exhibits the same clearance rate as LDL derived from VLDL1. LDL kinetic studies show a positive relationship between the amount of slowly catabolised LDL produced and the plasma triglyceride concentration across the “normal range” (B). Plasma triglyceride across the full range of normal through to severe hypertriglyceridemia exhibits a complex relationship to LDL cholesterol concentration and to LDL fractional catabolic rate (FCR) as shown in (C). Between triglyceride levels of 0.5 to about 3.0 mmol/l FCR falls and LDL concentration rises due to increased production of VLDL1 which…

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  Figure 3. Regulation of apolipoprotein B metabolism by key enzymes, receptors and cofactors. The main diagram depicts the known roles of lipoprotein and hepatic lipase (LpL, HL); cholesteryl ester transfer protein (CETP); apolipoproteins CII, CIII, and E; LDL receptor (LDL-r). The potential role of the VLDL receptor (VLDL-r), apoE receptor 2 (apoE-r2), and LDL receptor related protein 1 (LRP1) in VLDL1 removal is speculative. (A) Shows the relative quantitative importance of liver and body fat in regulating VLDL1 production and of apoCIII in controlling VLDL1 clearance [adapted from (43)]. The numerical values quoted are correlation coefficients.

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  Figure 4. Impact of alimentary lipemia on apolipoprotein B metabolism hypertriglyceridemia. The intestine can secrete chylomicrons, and particles in the VLDL density range during lipid absorption. The appearance of chylomicrons in the circulation impairs VLDL1 lipolysis as shown in (A). In an integrated multi-compartmental model, following a fat meal, VLDL1 apoB100 concentration increased and this was attributed to a drop in VLDL1 to VLDL2 transfer (i.e., reduced lipolysis rate) (29, 98). High density lipoprotein (HDL) via the agency of cholesteryl ester transfer protein (CETP) can transfer cholesteryl ester (CE) to triglyceride-rich lipoproteins thereby increasing their cholesterol content.

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  Figure 5. Mechanistic insights from pharmacological interventions. The diagram shows the known and putative actions of fibrates/selective peroxisome proliferator receptor α modulators (SPPARαM); fish oils (Omega-3 FA); statins; PCSK9 inhibitors (PCSK9i).