Postprandial lipaemia in familial combined hyperlipidaemia

Abstract

FCHL (familial combined hyperlipidaemia) is the most frequent inherited disorder of lipid metabolism leading to premature atherosclerosis. The usual phenotype in FCHL is elevated fasting plasma triacylglycerols, low HDL (high-density lipoprotein)-cholesterol concentrations and elevated plasma apolipoprotein B concentrations. The metabolic basis for this phenotype is hepatic overproduction of VLDL (very-low-density lipoprotein), which is only partly linked to the insulin resistance associated with FCHL. At this stage the molecular basis for this VLDL overproduction is not known, but emerging evidence points to a disturbed trapping of peripheral fatty acids, resulting in enhanced hepatic flux of NEFA [non-esterified ('free') fatty acids]. Postprandial hyperlipidaemia with accumulation of lipoprotein remnants and NEFA have been implicated in the development of atherosclerosis in this disorder. It has been proposed that, by VLDL overproduction, fasting hypertriglyceridaemia may lead to 'overflow' of the catabolic cascade for triacylglycerol-rich particles, thereby explaining the delayed catabolism of remnants in FCHL. Delayed clearance of remnants of VLDL and chylomicrons leads to enhanced interaction of these highly atherogenic particles with the endothelium, and enhanced trans-endothelial migration of the particles, resulting in a chronic inflammatory response that is the initiation of the atherosclerotic lesion. In this process, activated leucocytes (either directly by the remnants or indirectly by released NEFA) play an important role by adherence to the endothelium and migration into the subendothelial space, where the uptake of atherogenic remnants results in a vicious cycle of activation of endothelium, leucocytes and production of cytokines.

Familial Combined Hyperlipidemia: Current Knowledge, Perspectives, and Controversies

“…Along with TRL, diminished lipoprotein clearance associated to IR-mediated decreased LPL activity, leads to sdLDL and intermediate-density lipoprotein particle accumulation, both of which are highly atherogenic and easily oxidized, contributing to its entry into subendothelial pathways 3,43 . Decreased adiponectin levels in the setting of IR have been linked to higher levels of apoB and VLDL particles, further contributing to atherogenesis 44 , which might be feasible in the setting of FCHL.…”

Effects of a Stanol-Enriched Yogurt on Plasma Cholesterol Levels

“…Plant stanols decrease plasma cholesterol concentrations by reducing the intestinal absorption of cholesterol, thereby increasing the hepatic expression of LDL receptors and reducing the production of endogenous LDL cholesterol (5). This effect of stanols may reduce the risk of atherosclerosis (6). Combinations of plant stanols with antilipidemic drugs have been found to be more effective than individual usage, and an additional 17 % drop in serum cholesterol level was achieved using such a combination (7).…”

Thematic review series: Systems Biology Approaches to Metabolic and Cardiovascular Disorders Approaches to lipid metabolism gene identification and characterization in the postgenomic era

“…Here, we will consider only susceptibility genes for complex lipid-related disorders that have been identified by whole genome linkage and positional cloning. A striking example is the identification of a gene contributing to FCHL, which is characterized by increased serum cholesterol and triglyceride levels and is the most common familial lipid disorder predisposing to premature heart disease (89). Using whole genome scans in a Finnish population, a QTL for FCHL was identified on chromosome 1q21-23 (90).…”