Evidence from Lipoprotein Lipase Gene

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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-function 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. The lipid saturated the LPL gene might have a role in determin- (LOD¼2.1), between diastolic blood pressure macrophages evolve into foam cells and ing insulin sensitivity (P¼0.031, haplotype 1: (DBP) and marker D8S1145 (LOD¼1.06) then penetrate the endothelium cells into GATTCG) and insulin resistance (P¼0.007, and NEFL (LOD¼1.22) in the region of the middle layer of vascular wall.40 In addi- haplotype 4: GAGGGG) in their Mexican- 8p22 (LPL located on the region); two com- tion, the LPL could trigger other pro-patho- American population. Transgenic (Tg) wata- mon mutations HindIII (rs320; P¼0.004) genic events, such as the proliferation of nabe heritable hyperlipidemic (WHHL) and HinfI (rs328; P¼0.004) in the LPL gene smooth muscle cells.41 A marked decreases rabbits that overexpress the human LPL were both associated with DBP.31 In addition, in diet-induced atherosclerosis was detected gene were generated by Koike et al.In another quantitative-transmission/disequili- in chimerical mice that are deficient for addition to dramatically ameliorating hyper- brium test (TDT) also showed significant macrophage LPL expression,42 and athero- triglyceridemia and hypercholesterolemia, association between EH and D8S261 sclerosis was accelerated in transgenic apoE- overexpression of LPL was able to suppress (P¼0,0002 and 0.033 for SBP and DBP, deficient mice by macrophage-specific high-diet-induced obesity and insulin resis- respectively).32 The association of LPL and expression of human LPL.43 In the adipose tance in these Tg WHHL rabbits.26 However, hypertension was supported by another inde- and muscle tissues, however, LPL acts protec- two reports27,28 suggest that overexpression of pendent study in the Chinese Han popula- tively because it aids in the clearance of human LPL in skeletal muscle of mouse could tion, indicating that a polymorphism in circulating lipoprotein particles through sto- aggravate insulin resistance through the insu- intron 8 of PLP may be a risk variant for rage or utilization.6 lin signal cascade. A recent study found that EH (OR¼2.9, Po0.01).33 These findings the reduced LPL delivery in have not been replicated in Caucasian sam- LPL and AD skeletal muscle in skeletal muscle-specific ples34 and suggest that LPL might have a race- Recently, reports on the association between LPL knockout mouse (SMLPLÀ/À) induced specific role in the development of hyperten- LPL and AD have increased. No significant increased insulin sensitivity in skeletal muscle sion. The underlying mechanisms might distribution difference (P¼0.09) of S477X but insulin resistance in other metabolic include the effect of elevated TG on hemo- (rs328) is found between 852 patients with tissues, and ultimately led to obesity and dynamics, sodium re-absorption, retention AD and 190 healthy controls in Baum et al. systematic insulin resistance.29 These results and vascular hypertrophy,15 and the role of study,44 which is supported (P40.05) by the suggested that systematic overexpression of LPL in the regulation of arterial stiffness.31 Fidani et al. report.45 However, Blain et al.46 LPL might improve insulin resistance, study (in 153 patients with AD and 242 although the underlying mechanism is not LPL and CHD controls from Canada), on a PvuII SNP clear. These controversies suggest that the It is known that insulin resistance and hyper- polymorphism (rs285) of LPL, discovered association between the LPL gene and T2D tension are independent risk factors for CHD. that homozygote of P+ allele resulted in an may be tissue specific. Some results relevant On the basis of the linkage of the LPL gene to odds ratio of 2.3 for the risk of developing to the underlying mechanisms have been these factors, LPL is a candidate gene for AD; the P+ allele could significantly affect reported as follows: Cruz et al.29 study indi- CHD. A study by Socquard et al.35 in 404 its mRNA expression level (P¼0.026), cated that more FFA could be delivered to unrelated French patients with T2D found brain tissue cholesterol levels (P¼0.0013),

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stage or throughout their whole pathological Aberration process. Owing to the lipolytic function of of LPL gene LPL, it was considered a good candidate gene for these diseases. Catalytic function of LPL is 1 Dysfunction of the main basis in these relationships, deficient Hypertriglyceridemia antioxidation stress in AD synthesis or dysfunction of LPL reduces Dyslipidemia 5 brain hydrolysis of chylomicron and VLDL, hinder- 2 ing intake of lipids, and eventually resulting Induce insulin in redundant accumulation of lipoproteins in resistance 4 the plasma.6 The antioxidation stress function through of LPL promotes clearance of the lipid rem- the insulin 3 Atherosclerosis signal cascades and thromboembolism nants from the circulation, which are re- pancreatic esterified for storage and utilization in tis- Beta-cell 7–10,48–50 apoptosis sues. Dyslipidemia, induced by the aberration of the LPL gene, might be the Renal haemodynamics CHD shared intermediate process on the develop- Sodium reabsorption, EH ment of these five diseases. The hypertrigly- T2D Retention and Vascular hypertrophy ceridemia could directly be induced by the dysfunction of LPL. However, T2D, EH, CHD Figure 1 The schematic of the relationships among the lipoprotein lipase (LPL) gene and dyslipidemia, and AD are indirectly associated type II diabetes (T2D), essential hypertension (EH), coronary heart disease (CHD) and Alzheimer with LPL by different patho-physiological disease (AD). Dyslipidemia, induced by the aberration of the LPL gene, might be the shared mechanisms and signal pathways (see intermediate process on the development of these five diseases. Hypertriglyceridemia features dyslipidemia. Involves in regulating the pancreatic b-cell function, b-cell apoptosis and the insulin Figure 1). According to the findings reported signal cascades, which aggravates insulin insufficient secretion and insulin resistance and then induces here, we surmise that LPL’s antioxidation T2D. Hyperinsulinemia induced by elevated TG, may be partly responsible for EH by its functions on stress may be one important mechanism renal hemodynamics, sodium re-absorption, retention and vascular hypertrophy. Elevated TG is underlying the etiology of T2D, EH, CHD associated with atherosclerosis and thromboembolism; both of them are high-risk factors for the and AD, but more research is required to development of CHD. LPL has a role in the antioxidation stress of brain through lipids scavenging and elucidate this. Therefore, dyslipidemia and recycling, regarded as a protective factor for Alzheimer’s disease (AD). Dysfunction of antioxidation dysfunction of antioxidation stress induced stress induced by LPL aberration, in the brain, might be a risk factor of AD. by aberration of LPL gene might be two risk factors for the development of T2D, EH, neuro-fibrillary tangles (P¼0.025) and senile lipids by microglial cells in the brain.49,50 CHD and AD. plaque (P¼0.022) densities. In 243 Italian Thus, LPL secreted by microglial cells may Although evidence from the LPL gene patients with AD and 148 healthy subjects, not only help in the recycling of lipids but studies supports the hypothesis that there is the H+ allele of HindIII SNP (rs320) showed could also potentially act as a trophic factor a common biological basis for the common a trend but not strong association with AD, for neuronal survival and differentiation. AD complex diseases, a number of questions have the odds ratio was 2.7 (95% CI: 1.01À7.21; is considered as a neurodegenerative disease, also arisen from these studies that need to be P¼0.048); in addition, the homozygote of however, and multiple pieces of evidence investigated in more detail. First, the mole- H+H+ genotype could increase the risk of show that oxidative stress may also have a cular mechanisms that potentially link LPL to developing AD (P¼0.029).47 These discre- pathogenic role in AD.51 These results suggest T2D, EH, CHD and AD need specific atten- pancies may be attributed to one of the that LPL might have a role in the antioxidation in future research. Second, even for a following reasons. First, it is possible that tion stress of brain through lipids scavenging widely examined polymorphism, such as different ethnic groups may have different and recycling, bonding function and other S447X (rs328), reports from different ethnic risk alleles in the same gene or may have unrecognized mechanisms, and indicate that samples are not consistent and studies based different predisposing genes for AD. Second, LPL may be a protective factor of AD. There- on large and well-matched samples are it is possible that an independent study with fore, dysfunction of antioxidation stress required. Third, as described in this review, small samples has limited power to detect induced by LPL aberration, in the brain, tissue/cell-specific regulation of LPL has a association of small effect, and is prone to might be a risk factor of AD. More investiga- major implication for diseases, such as T2D false positives or negatives. Finally, false posi- tions of genetics and biology are required to and CHD; and this selective modulation of tives or negatives owing to statistical chance confirm the association between LPL and AD, LPL function is important for understanding cannot be completely eliminated. and to uncover the mechanism of LPL under- its pathological mechanism and finding new Findings from the neuroblastoma cells lying AD. therapeutic techniques. Fourth, an interesting suggest that LPL expression in neurons sti- issue for the future studies is whether or not mulates the extension of neuritis and protects DISCUSSION LPL might have a part in the development of the neurons against oxidized lipoproteins We have shown the existence of a common other diseases such as schizophrenia.52 toxicity.48 LPL overexpression was found in biological basis for several common complex In short, evidence from these studies of the lesion brain region in mouse models, and diseases. The examples given here support the LPL are consistent with that from Rzhetsky LPL mRNA level was upregulated in micro- idea that LPL is involved in several diseases et al.53 support the idea that separate genetic glial cells during ischemia produced by occlu- such as dyslipidemia, T2D, EH, CHD and diseases can overlap in their pathogenesis, sion of the middle cerebral artery, and was AD. Hypertriglyceridemia, T2D, EH, CHD especially for diseases that share similar involved in the scavenging and recycling of and AD, all display dyslipidemia in the initial clinical phenotypes. As phenotypic overlap

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is a good predictor of functional relatedness 10 Mamputu JC, Desfaits AC, Renier G: Lipoprotein 30 Jeunemaitre X, Soubrier F, Kotelevtsev YV et al:Mole- of the underlying susceptibility genes or lipase enhances human monocyte adhesion to aortic cular basis of human hypertension: role of angioten- 54 endothelial cells. J Lipid Res 1997; 38: 1722–1729. sinogen. Cell 1992; 71: 169–180. molecular mechanisms, these results indi- 11 Doolittle MH, Ben-Zeev O, Elovson J et al:The 31 Yang W, Huang J, Ge D et al: Lipoprotein lipase gene cate that one gene associated with multiple response of lipoprotein lipase to feeding and fasting. is in linkage with blood pressure phenotypes in diseases might exist in the population and Evidence for posttranslational regulation. JBiolChem Chinese pedigrees. 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Derek Morris from Trinity College Dublin and ide levels in coronary artery disease patients: the 37 Bos G, Scheffer PG, Vieira D et al: The relationship 447 anonymous peer reviewers for their valuable com- Ser -stop substitution in the lipoprotein lipase of lipoprotein lipase activity and LDL size is ments to the revision of this article. This work was gene. Circulation 1997; 95: 2628–2635. dependent on glucose metabolism in an elderly popu- 17 King H, Aubert RE, Herman WH: Global burden of partly supported by grants from Chongqing lation: the Hoorn Study. Diabetes Care 2004; 27: diabetes, 1995–2025: prevalence, numerical esti- 796–798. Medical University (No. 0124418029 and No. mates, and projections. 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