Triacylglycerol-rich lipoproteins and the generation of small, dense low-density lipoprotein

Abstract

LDL (low-density lipoprotein) is the major carrier of cholesterol in human plasma, and as such is intimately involved in the process of atherosclerosis. The lipoprotein class comprises a number of distinct subfractions, and is commonly divided into large, intermediate and small sized particles. Small, dense LDLs are held to be particularly atherogenic, since these particles are retained preferentially by the artery wall, are readily oxidized and carry an enzyme believed to have an important role in atherosclerosis, i.e. lipoprotein-associated phospholipase A(2). Generation of small, dense LDL occurs by intravascular lipoprotein remodelling as a result of disturbances such as Type II diabetes, metabolic syndrome, renal disease and pre-eclampsia. The key predisposing factor is the development of hypertriglyceridaemia, in particular elevation in the plasma concentration of large, triacylglycerol-rich VLDL (very-low-density lipoprotein). This leads to the formation of slowly metabolized LDL particles (5-day residence time), which are subject to exchange processes that remove cholesteryl ester from the particle core and replace it with triacylglycerol. LDL, so altered, is a potential substrate for hepatic lipase; if the activity of the enzyme is high enough, lipolysis will generate smaller, denser particles. Correction of the dyslipidaemia associated with small, dense LDL is possible using fibrates and statins, and this may contribute to the clinical benefits seen with these drugs. Fibrates act to lower plasma triacylglycerol (VLDL) levels, and so correct the underlying metabolic disturbance. Statins remove VLDL particles via receptor-mediated pathways and reduce the residence time (and hence limit the potential for remodelling) of LDL in the circulation.

Serum Lipid Alterations in Early Rheumatoid Arthritis Patients on Disease Modifying Anti Rheumatoid Therapy

“…Hypertriglyceridemia seems to be main predisposing factor for generation of sdLDL. When hepatic lipase activity increases it generates sdLDL by lipolysis [27]. We observed no significant difference in sdLDL levels post treatment.…”

De novo hepatic steatosis drives atherogenic risk in liver transplantation recipients

“…Overenrichment of VLDL particles coupled with subclinical insulin resistance in LTRs with hepatic steatosis may interfere with peripheral lipolysis of the VLDL particles, leading to the production of atherogenic sdLDL-C particles. 21 Alternatively, it is also possible that once LTRs develop hepatic steatosis and hypertriglyceridemia, hepatic production and secretion of sdLDL-C increases. 22 It is likely, though, that the increased sdLDL-C concentration observed in LTRs reflects a combination of both increased hepatic secretion and a marked decrease in catabolism of LDL apoB; however, additional studies are needed to examine this relationship further.…”

Effects of fenofibrate on atherogenic dyslipidemia in hypertriglyceridemic subjects

“…8 The threshold at which this shift in LDL subclass pattern occurs may be largely hereditary and, in a majority of individuals, appears to occur in the range of 100 to 200 mg/dl. Population data indicate that at a TG value of 200 mg/dl, the prevalence of pattern B is ~75% and when the TG is 100 mg/dl, the prevalence of pattern B is ~18%.…”

“…3,8,9 To investigate this issue in the present trial, we categorized subjects in the fenofibrate group based on end-of-treatment TG value and found a significant inverse relationship with the change in LDL particle diameter (p value for trend = 0.019). Those with end-of-treatment values < 200 mg/dl (n = 22) showed a medi- an increase of 0.56 nm, while those with end-of-treatment values between 200 and 299 mg/dl (n = 33) had a median increase of 0.31 nm, and those with end-of-treatment values ≥ 300 mg/dl (n = 29) showed essentially no change in LDL particle diameter (median increase = 0.02 nm).…”