Lipoprotein metabolism in familial hypercholesterolemia

Chemello, Kévin; García-Nafría, Javier; Gallo, Antonio; Martı́n, César; Lambert, Gilles; Blom, Dirk

doi:10.1016/j.jlr.2021.100062

Cited by 34 publications

(21 citation statements)

References 132 publications

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“…Beyond LDL cholesterol, female sex, non-smoking, high HDL cholesterol and hyperadiponectinemia were the main markers of longer CVD risk-free survival in HeFH. By contrast, no differences in HDL cholesterol concentrations were found in other studies when HeFH were compared with non-FH populations [28][29][30]. Therefore, environmental and genetic interactions involved in HDL metabolism could explain, at least in part, these discrepancies [17,18].…”

Section: Low Hdl Cholesterol Phenotype In Hefhmentioning

confidence: 67%

“…Notable evidence points to an altered macrophage-specific RCT in HeHF [43] (Figure 4). An impaired RCT, specifically related to the HDL2 subclass, with an inverse relationship between HDL efflux capacity and the development of atherosclerosis has been described in homozygous and HeFH patients [30]. Nevertheless, those patients were on high-intensity hypocholesterolemic therapy including LDL apheresis and RCT was assessed ex vivo.…”

Section: Defective Reverse Cholesterol Transport (Rct)mentioning

confidence: 99%

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Familial Hypercholesterolemia: Do HDL Play a Role?

2021

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Cardiovascular disease (CVD) in heterozygous familial hypercholesterolemia (HeFH), the most frequent monogenic disorder of human metabolism, is largely driven by low-density lipoprotein (LDL) cholesterol concentrations. Since the CVD rate differs considerably in this population, beyond the lifetime LDL cholesterol vascular accumulation, other classical risk factors are involved in the high cardiovascular risk of HeFH. Among other lipoprotein disturbances, alterations in the phenotype and functionality of high-density lipoproteins (HDL) have been described in HeFH patients, contributing to the presence and severity of CVD. In fact, HDL are the first defensive barrier against the burden of high LDL cholesterol levels owing to their contribution to reverse cholesterol transport as well as their antioxidant and anti-inflammatory properties, among others. In this context, the present narrative review aimed to focus on quantitative and qualitative abnormalities in HDL particles in HeFH, encompassing metabolic, genetic and epigenetic aspects.

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Section: Low Hdl Cholesterol Phenotype In Hefhmentioning

confidence: 67%

Section: Defective Reverse Cholesterol Transport (Rct)mentioning

confidence: 99%

Familial Hypercholesterolemia: Do HDL Play a Role?

2021

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“…The hepatic LDL receptor (LDLR) is a key regulator of LDL-apoB catabolism and genetic variants that reduce LDLR expression or function lead to elevated plasma LDL-C levels (24). Both male and female Trib1 Δhep mice on chow diets had significantly reduced hepatic abundance of Ldlr mRNA compared with control mice (Figure 2G and Supplemental Figure 3E), as well as reduced levels of LDLR protein (Figure 2H and Supplemental Figure 3F).…”

Section: Resultsmentioning

confidence: 99%

TRIB1 regulates LDL metabolism through CEBPα-mediated effects on the LDL receptor in hepatocytes

Quiroz-Figueroa¹,

Vitali²,

Conlon³

et al. 2021

Journal of Clinical Investigation

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“…LDLR could combine with LDLC and transport it to the lysosome for metabolism. The LDLR subsequently returns to the surface of liver cells for recycling ( van de Sluis et al, 2017 ; Chemello et al, 2021 ). Therefore, the pathogenic variants in LDLR could directly lead to protein dysfunction and LDLC metabolic disorders.…”

Section: Introductionmentioning

confidence: 99%

Two Novel Disease-Causing Mutations in the LDLR of Familial Hypercholesterolemia

Tian

et al. 2021

Front. Genet.

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As an autosomal dominant disorder, familial hypercholesterolemia (FH) is mainly caused by pathogenic mutations in lipid metabolism-related genes. The aim of this study is to investigate the genetic mutations in FH patients and verify their pathogenicity. First of all, a pedigree investigation was conducted in one family diagnosed with FH using the Dutch Lipid Clinic Network criteria. The high-throughput sequencing was performed on three family members to explore genetic mutations. The effects of low-density lipoprotein receptor (LDLR) variants on their expression levels and activity were further validated by silico analysis and functional studies. The results revealed that LDLC levels of the proband and his daughter were abnormally elevated. The whole-exome sequencing and Sanger sequencing were used to confirm that there were two LDLR missense mutations (LDLR c.226 G > C, c.1003 G > T) in this family. Bioinformatic analysis (Mutationtaster) indicated that these two mutations might be disease-causing variants. In vitro experiments suggested that LDLR c.226 G > C and c.1003 G > T could attenuate the uptake of Dil-LDL by LDLR. In conclusion, the LDLR c.226 G > C and c.1003 G > T variants might be pathogenic for FH by causing uptake dysfunction of the LDLR.

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Lipoprotein metabolism in familial hypercholesterolemia

Cited by 34 publications

References 132 publications

Familial Hypercholesterolemia: Do HDL Play a Role?

Familial Hypercholesterolemia: Do HDL Play a Role?

TRIB1 regulates LDL metabolism through CEBPα-mediated effects on the LDL receptor in hepatocytes

Two Novel Disease-Causing Mutations in the LDLR of Familial Hypercholesterolemia

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