Impaired chylomicron remnant clearance in familial combined hyperlipidemia.

The presence of increased TGs, defi ned as plasma TG levels >1.7 mM (150 mg/dl), occurs in 10-20% of the population in Western countries and is associated with increased risk of CVD ( 1 ). The etiology of hypertriglyceridemia is complex, and current therapeutic strategies to lower TG levels, including fi brates, PUFAs, and statins are available, yet their effi cacy with regard to lower CVD risk is not fully elucidated. Hence, the need for identification and characterization of additional pathways controlling synthesis and clearance of triglyceride-rich lipo proteins (TRLs) is ongoing, aiming to identify selective and potent targets for interventions. Although TG levels are routinely measured in a fasting state, observational studies have substantiated that nonfasting TG levels are in fact superior in predicting CVD risk ( 1-6 ). In this regard, the most important players involved in hepatic removal of TRLs are the LDL receptor (LDLr), the LDL receptor related protein 1 (LRP1), and heparan sulfate proteoglycans (HSPGs) ( 7-9 ). Of note, heterozygous Abstract Elevated nonfasting TG-rich lipoprotein levels are a risk factor for CVD. To further evaluate the relevance of LDLreceptor (LDLr) pathway and heparan sulfate proteoglycans (HSPGs) in TG homeostasis, we analyzed fasting and postprandial TG levels in mice bearing combined heterozygous mutations in both Exostosin (Ext) 1 and Ldlr , in subjects with hereditary multiple exostosis (HME) due to a heterozygous loss-of-function mutation in EXT1 or EXT2 (N = 13), and in patients with heterozygous mutations in LDLR [familial hypercholesterolemia (FH)] and SNPs in major HSPG-related genes (n = 22). Mice bearing a homozygous mutation in hepatic Ext1 exhibited elevated plasma TGs similar to mice lacking other key enzymes involved in HSPG assembly. Compound heterozygous mice lacking Ldlr and Ext1 showed synergy on plasma TG accumulation and postprandial clearance. In human subjects, a trend was observed in HME patients toward reduced postprandial TG clearance with a concomitant reduction in chylomicron clearance [area under the curve (AUC)-retinyl ester (RE) HME, 844 ± 127 vs. controls, 646 ± 119 nM/h, P = 0.09]. Moreover, in FH subjects with a high HSPG gene score, retinyl palmitate excursions were higher (AUC-RE, 2,377 ± 293 vs. 1,565 ± 181 nM/h, P < 0.05). Incremental AUC-apoB48 was similar between the groups. In conclusion, the data are supportive for a minor yet additive role of HSPG in human postprandial TG clearance, and further studies are warranted. -Mooij, H.

Section: Trl Clearance In Fhsupporting

confidence: 92%

Ext1 heterozygosity causes a modest effect on postprandial lipid clearance in humans

Mooij¹,

Moens²,

Gordts

et al. 2015

“…However, the uptake of LDL, albeit oxidized, by 3T3-L1 adipocytes was reported to increase cell proliferation and decrease cell differentiation (21)(22)(23). Moreover, multiple clinical studies have demonstrated that statin therapy, which reduces plasma concentrations of apoBlipoproteins, also improves plasma clearance of triglyceride (TG) (24)(25)(26)(27). Therefore, it is possible that elevated concentrations of apoB-lipoproteins not only are a consequence of dysfunctional WAT and hypertriglyceridemia but also play an active role in their pathology.…”

Section: Postprandial In Vivo Fat Clearancementioning

confidence: 99%

Low density lipoprotein delays clearance of triglyceride-rich lipoprotein by human subcutaneous adipose tissue

Bissonnette

Salem

Wassef

et al. 2013

This article is available online at http://www.jlr.org among the most common is reduced triglyceride-rich lipoprotein (TRL) clearance by peripheral tissue. White adipose tissue (WAT) is a major regulator of TRL clearance, particularly in the postprandial state ( 2-6 ). Following a meal, dietary fat enters the circulation in the form of chylomicrons, TRL with apoB48. Effi cient clearance of chylomicrons by WAT requires three sequential steps: i ) the hydrolysis of chylomicrons by endothelial lipoprotein lipase (LPL); ii ) the uptake of LPL-generated nonesterifi ed fatty acid (NEFA) by underlying adipocytes; and iii ) the utilization or storage of NEFA ( 3, 5 ). Dietary TRL remnants and NEFA that are not cleared by peripheral tissue are then taken up by the liver for utilization and resecretion as VLDL (TRL with apoB100).Healthy WAT is able to respond promptly to postprandial signals, such as insulin increasing the hydrolysis of dietary TRL and the uptake and storage of generated NEFA, thus reestablishing the homeostasis in plasma lipids. The storage versus the release of TRL-generated NEFA in human subcutaneous WAT was reported to be almost absent in the fasting state, to increase to 100% 1 h after the ingestion of a meal, and to decrease to 10-30% 6 h after the meal ( 5 ). Accordingly, delayed plasma clearance of postprandial TRL by WAT is believed to increase the infl ux of dietary TRL remnants and NEFA into nonadipose peripheral tissues, including muscle, pancreas, and liver, inducing lipotoxicity and insulin resistance ( 6-8 ). In the liver, this also leads to increased synthesis and secretion of VLDL, which further reduces chylomicron clearance due to competitive binding to LPL ( 9-14 ). Altogether, this increases the plasma concentrations of apoB-lipoproteins, which is measured as plasma apoB and represents mostly LDL particles (>90%) ( 14-16 ). Dysfunctional WAT is thus Postprandial hypertriglyceridemia is an independent risk factor for cardiometabolic disease ( 1 ). Many factors have been implicated in the etiology of hyperlipidemia;

“…Today, it is commonly accepted that the increased plasma triglycerides, total cholesterol, and apoB in FCHL are heterogeneous in origin, because they are the consequences of both an overproduction of VLDL particles and a decreased clearance of remnants (12)(13)(14). Therefore, researchers have stated that lipid levels are not the optimal phenotypical markers for elucidating the genetic background of FCHL (15).…”

mentioning

confidence: 99%

Heritability and genetic loci of fatty liver in familial combined hyperlipidemia

Brouwers

Cantor

Kono

et al. 2006

VLDL overproduction, a process that is driven by an excess amount of hepatic fat, is a well-documented feature of familial combined hyperlipidemia (FCHL). The aims of this study were to investigate whether fatty liver, measured with ultrasound and as plasma alanine aminotransferase (ALT) levels, develops against a genetic background in FCHL and to identify chromosomal loci that are linked to these traits. In total, 157 FCHL family members and 20 spouses participated in this study. Radiological evidence of fatty liver was more prevalent not only in FCHL probands (40%) but also in their relatives (35%) compared with spouses (15%) (P , 0.05). Heritability calculations revealed that 20-36% of the variability in ALT levels could be attributed to genetic factors. Nonparametric quantitative trait locus (QTL) analysis revealed three significant (P , 0.001) loci with either the ultrasound or the ALT trait in the male sample: 1q42.3, 7p12-21, and 22p13-q11; none was found in the female sample or the entire group. Of these QTLs, the 7p region was consistent over time, because reanalysis with ALT levels that were determined during a visit 5 years earlier yielded similar results. This study shows that fatty liver is a heritable aspect of FCHL. Replication of particularly the 7p region is awaited.-Brouwers,