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Evidence from Lipoprotein Lipase Gene

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Evidence from Lipoprotein Lipase Gene European Journal of Human Genetics (2010) 18, 3–7 & 2010 Macmillan Publishers Limited All rights reserved 1018-4813/10 $32.00 www.nature.com/ejhg VLDL, thereby providing non-festered fatty VIEWPOINT acids (NEFA) and 2-monoacylglycerols for many tissues.8,9 In adipose, NEFA is re- esterified for storage in the form of triacyl- The common biological basis for glycerol (TAG); but in muscles, oxidation of NEFA is the major source of energy.6 Accord- common complex diseases: ing to these studies above, it might be reason- able to considering LPL as the preferred evidence from lipoprotein lipase candidate gene for the dyslipidemia. The relationship between LPL and gene dyslipidemia is very well established and independent of ethnic background.1–3,13 Cui Xie1, Zeng Chan Wang1,XiaoFengLiu2 and Mao Sheng Yang*,1 Several clinical observations have suggested that the patients with LPL deficiency suffer 3,14 The lipoprotein lipase (LPL) gene encodes a rate-limiting enzyme protein that has a severe hypertriglyceridemia. The genetic key role in the hydrolysis of triglycerides. Hypertriglyceridemia, one widely prevalent variants of LPL may have a role in determin- 15 syndrome of LPL deficiency and dysfunction, may be a risk factor in the ing lipid levels. A study by Jemaa et al. in development of dyslipidemia, type II diabetes (T2D), essential hypertension (EH), French patients (614 patients with myocardial coronary heart disease (CHD) and Alzheimer’s disease (AD). Findings from earlier infarction and 733 controls; Po0.01) indi- studies indicate that LPL may have a role in the pathology of these diseases and cated that there is an association between - therefore is a common or shared biological basis for these common complex LPL rs328 C G (Ser447Stop) polymorphism diseases. To examine this hypothesis, we reviewed articles on the molecular and hypertriglyceridemia. Their result is 16 structure, expression and function of the LPL gene, and its potential role in the supported by Groenemeijer et al. study in etiology of diseases. Evidence from these studies indicate that LPL dysfunction is Dutch patients (820 patients of coronary involved in dyslipidemia, T2D, EH, CHD and AD; and support the hypothesis that artery disease; P¼0.044), and by King et al. 17 18 there is a common or shared biological basis for these common complex diseases. (1998) finding and Yamada et al. report (in 5213 Japanese individuals; P¼0.0007). European Journal of Human Genetics (2010) 18, 3–7; doi:10.1038/ejhg.2009.134; The above results are also supported by published online 29 July 2009 evidence from the Chinese samples. A genetic screen of LPL gene of 53 hypertriglyceridemia Keywords: lipoprotein lipase (LPL) gene; shared biological basis; common complex patients in 26 T2D Chinese pedigrees identi- diseases fied that three novel mutations, Lys312insC, Thr361LnsA and double mutations INTRODUCTION monoacylglycerol for tissue use.6 Recently, in Lys312insC+Asn291Ser, were clinically asso- The lipoprotein lipase (LPL) gene is located addition to hydrolysis, LPL has been reported ciated with hypertriglyceridemia, which was on 8p22, spans B30 kb and contains 10 exons to be involved in lipid intake and clearance.7–10 further confirmed by the mutagenesis with and encodes a rate-limiting enzyme called Variations in LPL gene sequence, expression significantly reduced LPL activity (Po0.01) lipoprotein lipase. LPL has a key role in the and regulation may influence its function and and expression studies.19 Yang et al.20 found hydrolysis of triglycerides (TG). In 1960, LPL contribute to diseases. The changes in LPL that two SNPs HindIII (rs320) and HinfI deficiency was discovered by Havel and activity in adipose and muscle tissues suggest (rs328) at LPL were associated with choles- Gordon,1 and several mutations were identi- that LPL is regulated in a tissue-specific terol levels (P¼0.0178 and P¼0.0088, respec- fied upon cloning the gene in 1991 by manner.4,11,12 Several allelic variants were re- tively) in Chinese cohort. Henderson et al.2 Subsequently, more subtle ported to affect the expression and activity of This association is further validated by LPL mutations were detected in the LPL gene, and LPL. In this paper, we review the literature target therapy studies. Ross et al.21 observed some mutants are reputed to influence LPL relating to LPL focusing on five diseases, that intramuscular administration of an activity and has a role in the disease’s namely dyslipidemia, type II diabetes adeno-associated virus serotype 1 (AAV1) etiology.2–3 LPL is one member of the trigly- (T2D), essential hypertension (EH), coronary vector encoding the human LPLS447X variant ceride (TG) lipase gene family, which includes heart disease (CHD) and Alzheimer’s disease cDNA (AAV1-LPLS447X) could normalize the pancreatic lipase (PL), hepatic lipase (HL) and (AD) to see whether there is any common dyslipidemia in LPLÀ/À mice, and Kodera newly discovered endothelium lipase (EL).4 It etiological mechanism involving LPL. et al. reported that anti-LPL autoantibody is a rate-limiting enzyme in the hydrolysis of could elevate serum triglyceride levels by triglyceride-rich particles,5 such as chylomi- LPL and dyslipidemia inhibiting 47% activity of LPL (Po0.0001).22 cron and very-low-density lipid (VLDL), LPL is the key enzyme in the hydrolysis of thereby providing non-ester acids and 2- triglycerides packaged in chylomicron and LPL and T2D T2D is widely prevalent in the world’s popu- 1Laboratory of Disorder Genes, School of Public Health, Chongqing University of Medical Sciences, Chongqing, lations and it is predicted that the prevalence 17 People’s Republic of China; 2Chongqing Medical University Library, Chongqing, People’s Republic of China will increase to 5.4% by the year 2025. Both hereditary and environmental factors contri- *Correspondence: Professor MS Yang, Laboratory of Disorder Genes, Chongqing University of Medical Sciences, bute to individual susceptibility; however, School of Public Health, PO Box 109, 1 Yi Xue Yuan Road, Chongqing, 400016, People’s Republic of China. Tel: +00 86 23 6848 6014; Fax: +00 86 23 6848 5111; E-mail: [email protected] dysfunction of LPL may explain, at least in Received 25 September 2008; revised 19 May 2009; accepted 26 June 2009; published online 29 July 2009 part, the prevalence of T2D. Common biological basis for common complex diseases CXieet al 4 Ho¨lzl et al.23 reported a study that enrolled pancreatic b-cells by increasing LPL activity, that the prevalence of CHD in this popula- 85 heterozygous carriers of a missed (Gly188- consequently impairing b-cell function and tion was 18%, but increased to 29 and 38% in Glu) mutation or a splice site mutation (c-in promoting apoptosis in the patients with H2H2 (rs320, the site of HindIII) and P2P2 position-3 at the acceptor splice site of intron hyperglyceridemia, hyperinsulinemia and (rs285, the site of PvuII), respectively, poly- 6) in the LPL gene and 108 non-carriers. T2D. Hypertriglyceridemia prioritizing the morphism carriers at LPL (Po 0.02). The Their results indicated that the heterozygous utilization of TAG as fuels inhibits the intake findings by Zee et al.36 indicated that LPL carriers had elevated triglyceride level and and oxidization of glucose;27 intracellular N291S (rs268) genetic variant is an indepen- reduced insulin sensitivity compared with fatty acid metabolites interfere with propaga- dent predictor of increased risk of venous non-carriers (Po0.0005 and P¼0.014, tion of insulin signaling cascade;28 and deli- thromboembolism (OR¼3.09; 95% CI: respectively). A meta-analysis including vering more FFA to pancreatic b-cells impairs 1.56–6.09; P¼0.001), also supporting a role 19 246 individuals showed nominal signifi- b-cell function and promote apoptosis.29 The for the LPL gene in vascular biology. One cant association between LPL N291S (rs268) above findings may be partly responsible for study among 2484 inhabitants of the munici- variant and T2D (odds ratio¼2.26, 95% the association between LPL and T2D. pality of Hoorn discovered that low LPL confidence interval (CI): 1.02–4.99, P¼0.04) activity and high triglyceride concentration and CHD (odds ratio¼1.48, 95% CI: 1.09– LPL and EH are determinants of small LDL size,37 which is 2.00, P¼0.01). Although not convincing, The occurrence of EH is affected by heredi- associated with increased risk of cardiovascu- together with the powerful correlation tary and environmental factors and interac- lar disease (CVD).38 The naturally occurring between significantly decreased catalytic tion between them.30 Many previous findings LPL S447X, which was shown to increase the activity (B60% of the wild type) and secre- have shown that abnormal lipid metabolism lipolytic function of LPL and a gain-of-func- tion ability (about 50% of the wild type) of and insulin resistance may have a role in the tion mutation, could reduce the CVD risk N291S mutant and deleterious lipid profile process of EH. LPL, hydrolyzing TG and compared with S447S.39 All of these observa- (triglycerides: 32.3% increase and HDL-C: regulating lipid metabolism, is logical to be tions suggest that LPL might involve in the 34.2% decrease), which are risk factors of regarded as the candidate gene for EH. etiology of CHD. However, the underlying T2D and CHD, this association may be not Linkage analysis of 148 Chinese hyper- mechanism is complicated and tissue specific. a false-positive result and further study is tensive pedigrees with seven micro-satellite Overexpression of LPL in monocyte-derived necessary and justifiable.24 Goodarzi et al.25 makers of LPL gene discovered links macrophages (MDM) induces unregulated analyzed haplotypes of six polymorphisms in between systolic blood pressure (SBP) and uptake of NEFA and 2-monoacyglycerol and LPL and provided compelling evidence that marker D8S261 (LOD¼2.68) and NEFL re-esterified into TAG.
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