Low-density Lipoprotein Receptor Genotypes Modify the Sera Metabolome of Patients with Homozygous Familial Hypercholesterolemia

Overview

Journal iScience

Publisher Cell Press

Date 2022 Nov 3

PMID 36325061

Authors

Zhiyong Du

Fan Li

Linyi Li

Yu Wang

Jianping Li

Ya Yang

Long Jiang

Luya Wang

Yanwen Qin

Affiliations

Soon will be listed here.

Abstract

Homozygous familial hypercholesterolemia (HoFH) is an extremely rare metabolism disorder usually caused by low-density lipoprotein receptor (LDLR) mutations. LDLR genotype is commonly known to determine blood concentrations of LDL cholesterol. However, effects of LDLR genotype on holistic metabolome remain unclear. Herein, we present metabolomic, genetic, and clinical datasets from a large multi-center panel of 142 patients with LDLR-mutated HoFH. We found that true homozygotes and compound heterozygotes showed few differences in clinical and metabolomic phenotypes. Compared with defective/defective mutation carriers, patients carrying one or two null mutation showed profound alterations in clinical laboratory lipids and serum cholesterol esters, lysophosphocholines, bile acids, and amino acids. Importantly, these altered metabolites are implicated in multiple biochemical reactions and associated with LDL cholesterol. This study extends the first map of different LDLR genotypes influencing the metabolome and suggests that the small-molecule metabolites serve as potential targets to mitigate the deleterious impact of LDLR mutations on HoFH.

Citing Articles

The prognostic and therapeutic significance of polyunsaturated fatty acid-derived oxylipins in ST-segment elevation myocardial infarction.

Du Z, Lu Y, Ma Y, Yang Y, Luo W, Liu S Imeta. 2025; 4(1):e266.

PMID: 40027487 PMC: 11865345. DOI: 10.1002/imt2.266.

Targeting Lysophosphatidic Acid Ameliorates Dyslipidemia in Familial Hypercholesterolemia.

Du Z, Wang Y, Li F, Sun X, Du Y, Li L Research (Wash D C). 2025; 8:0629.

PMID: 40018730 PMC: 11865365. DOI: 10.34133/research.0629.

Effects of -2 Palmitic Triacylglycerols and the Ratio of OPL to OPO in Human Milk Fat Substitute on Metabolic Regulation in Sprague-Dawley Rats.

Zhu L, Fang S, Zhang Y, Sun X, Yang P, Lu W Nutrients. 2024; 16(9).

PMID: 38732546 PMC: 11085268. DOI: 10.3390/nu16091299.

Metabolomic and lipidomic studies on the intervention of taurochenodeoxycholic acid in mice with hyperlipidemia.

Cui N, Zhang W, Su F, Zhang Z, Li B, Peng D Front Pharmacol. 2023; 14:1255931.

PMID: 38034994 PMC: 10684951. DOI: 10.3389/fphar.2023.1255931.

Metabolomic epidemiology offers insights into disease aetiology.

Fuller H, Zhu Y, Nicholas J, Chatelaine H, Drzymalla E, Sarvestani A Nat Metab. 2023; 5(10):1656-1672.

PMID: 37872285 PMC: 11164316. DOI: 10.1038/s42255-023-00903-x.

References

Cuchel M, Bruckert E, Ginsberg H, Raal F, Santos R, Hegele R . Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J. 2014; 35(32):2146-57. PMC: 4139706. DOI: 10.1093/eurheartj/ehu274. View

Zhou Y, Little P, Ta H, Xu S, Kamato D . Lysophosphatidic acid and its receptors: pharmacology and therapeutic potential in atherosclerosis and vascular disease. Pharmacol Ther. 2019; 204:107404. DOI: 10.1016/j.pharmthera.2019.107404. View

Sniderman A, Glavinovic T, Thanassoulis G . Key Questions About Familial Hypercholesterolemia: JACC Review Topic of the Week. J Am Coll Cardiol. 2022; 79(10):1023-1031. DOI: 10.1016/j.jacc.2022.01.010. View

Thompson G, Blom D, Marais A, Seed M, Pilcher G, Raal F . Survival in homozygous familial hypercholesterolaemia is determined by the on-treatment level of serum cholesterol. Eur Heart J. 2017; 39(14):1162-1168. DOI: 10.1093/eurheartj/ehx317. View

Luirink I, Braamskamp M, Wiegman A, Hartgers M, Sjouke B, Defesche J . The clinical and molecular diversity of homozygous familial hypercholesterolemia in children: Results from the GeneTics of clinical homozygous hypercholesterolemia (GoTCHA) study. J Clin Lipidol. 2019; 13(2):272-278. DOI: 10.1016/j.jacl.2018.12.003. View

Santos R, Gidding S, Hegele R, Cuchel M, Barter P, Watts G . Defining severe familial hypercholesterolaemia and the implications for clinical management: a consensus statement from the International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel. Lancet Diabetes Endocrinol. 2016; 4(10):850-61. DOI: 10.1016/S2213-8587(16)30041-9. View

Claria J, Curto A, Moreau R, Colsch B, Lopez-Vicario C, Lozano J . Untargeted lipidomics uncovers lipid signatures that distinguish severe from moderate forms of acutely decompensated cirrhosis. J Hepatol. 2021; 75(5):1116-1127. DOI: 10.1016/j.jhep.2021.06.043. View

Zurkinden L, Sviridov D, Vogt B, Escher G . Downregulation of by Cholic Acid and Chenodeoxycholic Acid in Double Knockout Mice: Differential Cardiovascular Outcome. Front Endocrinol (Lausanne). 2020; 11:586980. PMC: 7656987. DOI: 10.3389/fendo.2020.586980. View

Cuchel M, Meagher E, du Toit Theron H, Blom D, Marais A, Hegele R . Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet. 2012; 381(9860):40-6. PMC: 4587657. DOI: 10.1016/S0140-6736(12)61731-0. View

10.

Alves A, Alonso R, Diaz-Diaz J, Medeiros A, Jannes C, Merchan A . Phenotypical, Clinical, and Molecular Aspects of Adults and Children With Homozygous Familial Hypercholesterolemia in Iberoamerica. Arterioscler Thromb Vasc Biol. 2020; 40(10):2508-2515. DOI: 10.1161/ATVBAHA.120.313722. View

11.

Luo J, Yang H, Song B . Mechanisms and regulation of cholesterol homeostasis. Nat Rev Mol Cell Biol. 2019; 21(4):225-245. DOI: 10.1038/s41580-019-0190-7. View

12.

Argmann C, Houten S, Zhu J, Schadt E . A Next Generation Multiscale View of Inborn Errors of Metabolism. Cell Metab. 2015; 23(1):13-26. PMC: 4715559. DOI: 10.1016/j.cmet.2015.11.012. View

13.

Basu S, Duren W, Evans C, Burant C, Michailidis G, Karnovsky A . Sparse network modeling and metscape-based visualization methods for the analysis of large-scale metabolomics data. Bioinformatics. 2017; 33(10):1545-1553. PMC: 5860222. DOI: 10.1093/bioinformatics/btx012. View

14.

Wu Y, Jiang L, Zhang H, Cheng S, Wen W, Xu L . Integrated analysis of microRNA and mRNA expression profiles in homozygous familial hypercholesterolemia patients and validation of atherosclerosis associated critical regulatory network. Genomics. 2021; 113(4):2572-2582. DOI: 10.1016/j.ygeno.2021.05.036. View

15.

Larrea-Sebal A, Benito-Vicente A, Fernandez-Higuero J, Jebari-Benslaiman S, Galicia-Garcia U, Uribe K . MLb-LDLr: A Machine Learning Model for Predicting the Pathogenicity of Missense Variants. JACC Basic Transl Sci. 2021; 6(11):815-827. PMC: 8617597. DOI: 10.1016/j.jacbts.2021.08.009. View

16.

Kim M, Yoo H, Lee D, Lee J . Oxidized LDL induces procoagulant profiles by increasing lysophosphatidylcholine levels, lysophosphatidylethanolamine levels, and Lp-PLA activity in borderline hypercholesterolemia. Nutr Metab Cardiovasc Dis. 2020; 30(7):1137-1146. DOI: 10.1016/j.numecd.2020.03.015. View

17.

Jiang L, Benito-Vicente A, Tang L, Etxebarria A, Cui W, Uribe K . Analysis of LDLR variants from homozygous FH patients carrying multiple mutations in the LDLR gene. Atherosclerosis. 2017; 263:163-170. DOI: 10.1016/j.atherosclerosis.2017.06.014. View

18.

Guijas C, Montenegro-Burke J, Warth B, Spilker M, Siuzdak G . Metabolomics activity screening for identifying metabolites that modulate phenotype. Nat Biotechnol. 2018; 36(4):316-320. PMC: 5937131. DOI: 10.1038/nbt.4101. View

19.

Irvine H, Acharjee A, Wolcott Z, Ament Z, Hinson H, Molyneaux B . Hypoxanthine is a pharmacodynamic marker of ischemic brain edema modified by glibenclamide. Cell Rep Med. 2022; 3(6):100654. PMC: 9244997. DOI: 10.1016/j.xcrm.2022.100654. View

20.

Chen P, Chen X, Zhang S . Current Status of Familial Hypercholesterolemia in China: A Need for Patient FH Registry Systems. Front Physiol. 2019; 10:280. PMC: 6435575. DOI: 10.3389/fphys.2019.00280. View