LPL and Triglycerides Metabolism

LPL is ubiquitously expressed in the whole body. High expressions are found in the adipose tissue, cardiac and skeletal muscles, and the lactating mammary gland. Relatively lower expressions are found in macrophages, hormone-producing cells in the adrenals and ovaries, certain neuronal cells, thoracic aorta, spleen, testes, lung, and kidney. The expression and activity of LPL are regulated at transcriptional, posttranscriptional, translational and posttranslational levels, and in a tissue-specific manner. The basal transcription of LPL is controlled by Oct-1, the NF-Y binding motifs, the 5-CCTCCCCC-3 motif, Sp1, and Sp3. Induced transcription in response to food intake is regulated through the peroxisome proliferator response element (PPRE) and the sterol regulatory element. Both elements are controlled by hormonal and inflammatory stimuli, such as insulin, glucocorticoid, adrenaline, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, and interleukin (IL)-1β. Posttranscriptional, translational and posttranslational regulation ensures the tissue specificity, localization and activation of LPL (Mead et al, 2002; Wang & Eckel, 2009).

Although the function of LPL is at the luminal surface of the capillary endothelium, it is not expressed in these cells. Instead it is first synthesized in parenchymal cells and then translocated to its site of action (Fig.2). The newly synthesized LPL is an inactive monomer composed of two structurally distinct regions. The amino-terminal domain is responsible for catalysis and the carboxyl-terminal domain is for the lipoprotein substrate binding. After post-translational modification in the Golgi apparatus of the parenchymal cells, active form of LPL is formed by dimmerization.  It is then secreted and translocated to the luminal surface of the capillary endothelium where the LPL dimmer is tethered to the cell surface by heparin sulfate proteoglycans (HSPG). Upon binding to and activation by the APO CII component of VLDL and chylomicron, the enzymatic activity of LPL is fully activated, the TG components of the lipoproteins are hydrolyzed, free fatty acids released.

Figure 2. Posttranslational modifications and capillary endothelium (EC) localization of LPL (red circles). Heparin sulfate proteoglycans (HSPG, shown as the tree branches) and GPIHBP1 (glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1) bind LPL to immobilize the enzyme on the EC surface where it captures VLDL and CM (chylomicrons) to release free fatty acids from the triglycerides in the lipoproteins . ER, endoplasmic reticulum; G, Golgi apparatus; SV, secretory vesicle (Adopted from Wang & Eckel, 2009).

Due to its critical role in fatty acids releasing from the TG-rich lipoproteins VLDL and chylomicrons, LPL activity is indispensible for animal survival. LPL knock-out mice have three fold increased plasma TG concentration and seven fold increased VLDL accumulation after birth.  These mice suffer chylomicronemia and die within 24 h either from ischemia or from hypoglycemia as a result of the inability to process the lipid nutrients in milk. Mice with heterozygous LPL deficiency (LPL+/-) have somewhat lower levels of fasting plasma glucose with relative hyperinsulinemia, presumably due to increased insulin secretion in responding to reduced LPL expression. In these mice the fat mass/lean mass ratio difference generally increases over time, indicating an age-dependent excessive accumulation of body fat. In contrast, over-expression of LPL in mice confers a protective phenotype, improving clearance of both chylomicron and VLDL and reducing plasma TG concentration nearly 75% (Johansen et al, 2011). In humans, lowering or deficiency of LPL expression is associated with hyperlipidemia (Mead et al, 2002). Elevated TG due to LPL activity deficiency also increases the risk for cancer (Tskasu et al, 2012).

LPL activity also affects the HDL (high density lipoproteins) level in blood circulation.  HDL is mainly synthesized in the liver.  In blood circulation, TG and cholesteryl ester are constantly transferred between HDL and TRLs (Fig. 1).  A decreased LPL activity leads to accumulation of chylomicron and VLDL, which enhances the transfer of TG to HDL, converting the later into a LDL-like lipoprotein, leading to decreased HDL concentration and increased risk for cardiovascular diseases.

One remarkable feature of LPL regulation is its differential tissue specific responses to food, hormonal factors, and to health status. For example, in adipose tissue, LPL is increased by insulin and food intake while decreased by fasting. In contrast, LPL activity in skeletal muscle is increases in responding to insulin and fasting. When an individual becomes obese, adipose tissue LPL is increased per cell but no longer responsive to insulin and food intake. When an individual becomes diabetic, LPL activity is reduced in both adipose and skeletal muscle (Table 2). This tissue specific LPL regulation plays important role in the pathology of LPL deficiency symptoms. It might be responsible for the paradox that although the Hind III H-/H- genotype is associated with lower blood TG and high HDL levels,  it is also associated with higher risks for insulin resistance and type 2 diabetes.

Table 2. Tissue specific LPL activity in response to environmental factors (Derived from Wang & Eckel, 2009).

Stimuli	Adipose Tissue	Skeletal Muscle
Fasting	↓	↑
High carb diet	↑↑	↑
High fat diet	↑	↑
Exercise	Variable	↑
Insulin	↑↑	↓
Catecholamine	↓	No effect
Thyroid hormone	↑	↓
Estrogen	↓	↑
Testosterone	↓	↑
Obesity	↑↑	↓
Diabetes	↓	↓

LPL Polymorphism

The human LPL gene is located on the short arm of chromosome 8. More than 100 mutations of LPL gene have been identified and about 40 mutations that cause clinical symptoms lipoprotein lipase deficiency or familial combined hyperlipidemia have been described in the OMIM (Online Mendelian Inheritance in Man) database here.  Four of them, T-93G (rs1800590), D9N (rs1801177), G188E (rs118204057) and N291S (rs268) are distributed in Caucasian only with frequency of 1.6%, 2.1%, 0.03% and 2.5% respectively. The rest are very rare. Nevertheless, carriers of these mutations generally require clinical attention and are normally prescribed with strict low-fat diet.  They will not be discussed here further due to the low prevalence. Three common polymorphisms, including the gain-of-function mutation S477X and two restriction fragment length polymorphism (RFLP) Pvu II and Hind III, have been identified systematically associated with plasma TG and HDL concentrations, and CVD risk. These three common polymorphisms are the focus of this review.

The S477X polymorphism (rs328), also known as Ser477Stop or Ser477Ter, is caused by a C to G transversion at nucleotide 1595 located in exon 9 of the LPL gene. This transversion changes the codon for amino acid serine into a stop codon at position 447 of the protein, leading to the removal of the last two amino acid residues at the C-terminal. The truncated LPL protein has an increased LPL activity of 18-36%, due to mechanisms that has not been unequivocally demonstrated (Rip et al, 2006).

The Hind III RFLP (rs320) occurs in intron 8 of the LPL gene with a T to G transition. The major allele (T allele) renders the DNA susceptible to the restriction enzyme Hind III cutting.  It is therefore also referred to as the H+ allele in literature.  Correspondingly, the minor allele (G allele) abolishes the Hind III cutting site and is referred to as H- allele in literature.

The Pvu ll RFLP (rs285) located in intron 6 of the LPL gene with a C to T transition. The major allele (C allele) renders the DNA susceptible to the restriction enzyme Pvu II cutting.  It is therefore also referred to as the P+ allele in literature.  Correspondingly, the minor allele (T allele) abolishes the Pvu II cutting site and is referred to as P- allele in literature.

The minor alleles of all three polymorphisms have been associated with decreased TG and increased HDL in carriers. The minor allele frequencies of S477X, Hind III RFLP and Pvu II FRLP are 10%, 29%, and 46% respectively in general population. The allele distribution shows not much difference among all ethnic groups (Table 1; Sagoo et al, 2008).

Since both the Hind III and Pvu II RFLPs occur in introns, their impact on blood TG and HDL levels are suspected due to linkage disequilibrium with functional variants.  Indeed it is reported both FRLPs are strongly linked to the S477X polymorphism (Sagoo et al, 2008). For example, analysis in Caucasians showed that only three haplotypes existed: H+/S447, H-/S447, and H-/X447 (Humphries et al, 1998; Corella et al, 2002). The H+/S447 haplotype was associated with the least favorable TG and HDL profile and the H-/X447 was associated with the best. A representative haplotype genotype distribution is shown in the table below.

Table 3. Hind III RFLP and S447X haplotype frequency in Caucasians (derived from Corella et al, 2002).

		S447X
		S/S	S/X	XX
Hind III	H+/H+	47%	0	0
	H+/H-	24%	19%	0
	H-/H-	3%	5%	2%

Disease Associations

Many studies have investigated the interaction of LPL polymorphisms and serum lipid profiles.  It has been consistently demonstrated that the minor alleles of all three LPL polymorphisms mentioned here are associated with lower TG and increased HDL levels, thus lower risk for cardiovascular diseases. A recent meta-analysis of 26 studies of S447X, 23 studies of Hind III RFLP, and 18 studies on the Pvu II RFLP involving subjects in Caucasians and Asians concludes that the TG lowing and HDL increasing effect of the minor alleles renders their carriers reduced risks for cardiovascular diseases, with odd ratios of 0.84, 0.89 and 0.96 respectively (Sagoo et al, 2008).

The associations of theses polymorphisms with other diseases have also been reported but lack consistency or replication.  For example, the X allele of the S447X polymorphism has also been associated with lower blood pressure, lower risk for Alzheimer disease (Rip et al, 2006) and higher risks for pancreatic calcification and steatorrhea in hyperlipidemic pancreatitis (Chang et al, 2009). In a Japanese study it is found that the minor X-allele carriers has a much higher prostate cancer than the SS genotypes (odds ratio = 1.625) while this association was not found for Hind III and Pvu II polymorphisms (Narita et al, 2004). In another study involving Han Chinese, it was found that although individuals with the Hind III H-/H- genotype tended to have lower triglyceride levels but an unexpected 2.12-fold increased risk (odds ratio: 3.12) for type 2 diabetes when compared to the H+/H+ genotype carriers (Qi et al, 2011). This observation echoes a previous report that a haplotype including the X allele of S447X and the H- allele of Hind III is associated with increased insulin resistance in Mexican Americans (Goodarzi et al, 2004). The mechanisms of such associations are not fully understood but are suspected to be related to the differential regulation of LPL activity in adipose tissue and in skeletal muscles.

Dietary Interactions

Since the main function of LPL is to hydrolyze TG in lipoproteins to release free fatty acids, its activity is critical for TG-rich lipoprotein clearance. Lower LPL activities of the major alleles of S447X, Hind III RFLP, Pvu II RFLP are expected to have lower TG clearance capability than the minor alleles.  In optimal dietary condition, the LPL activity between the major allele and the minor alleles may not be evident. But when challenged by higher TG-rich lipoprotein synthesis, such as in the case of high-fat diet or excess calorie, the defects in lypolysis of the major alleles are unmasked, the unfavorable responses manifest.
When the effect of S447X on lipid and lipoprotein response to dietary saturated fat was examined in 214 healthy Israel subjects (Friedlander et al, 2000), triglyceride baseline (LSF diet, 7.4% of total energy was from saturated fat) values were significantly lower and the HDL baseline levels were slightly higher in X allele carriers than in SS genotypes. Upon switching to a HSF diet (12.6% of total energy was from saturated fat) for 4-weeks, the TG and HDL levels were increased in all subjects.  But the increase of TG was about 4.4-fold in SS genotypes as in the X allele carriers. On the contrary, the increase of HDL was less than half of the increase in X allele carriers (Table 4).  These results demonstrated the unfavorable response to high SF in SS genotypes.

Table 4. LPL-S447X genotypes in response to LSF diet to HSF diet switch (data derived from Friedlander et al, 2000). Baseline represents the level at LSF (low-saturated-fat) diet.  Change represents the amount increased due to switching to HSF (high-saturated-fat) diet.

Genotypes		SS	SX
TG (mg/ml)	Baseline	159.6	120.4
	Change	2.2	0.5
HDL (mg/ml)	Baseline	37.3	37.9
	Change	1.1	2.5

In a study to assess the effects of interactions between a low-calorie diet and the Hind III polymorphism on plasma lipids, 115 unrelated overweight French patients (77 women and 38 men) recruited on the basis of 120% of ideal body weight were subject to a diet intervention with 25% restriction in energy intake for 2.5 months. Before the intervention, lipid and lipoproteins differed significantly between Hind III genotypes. Homozygous subjects for the H+/H+ had significantly higher plasma and VLDL-TG and apolipoprotein B concentrations than subjects carrying H- allele. After the diet intervention, H+/H+ subjects reduced their VLDL-TG and apolipoprotein B concentrations more than H- carriers, in such a way that differences in lipid levels according to genotypes were no more significant after diet (Table 5). The magnitude of the decrease in TG was positively correlated with the initial concentration but, among hypertriglyceridemic subjects, H+H+ still had the largest decrease in plasma and VLDL-TG. These data support the theory that subjects with the H+H+ genotype are predisposed to hypertriglyceridemia in response to calorie excess but they are good responders to diet restriction in terms of lipid levels (Jemaa et al, 1997).

Table 5. Interaction of Hind III genotypes with calorie restriction diet on plasma triglycerides (TG) and lipoprotein B levels.

Genotypes		H-/H- & H-/H+	H+H+
Plasma TG (mmol/l)	Before intervention	1.07	1.39
	After intervention	1.03	1.12
VLDL-TG (mmol/l)	Before intervention	0.62	0.88
	After intervention	0.57	0.61
ApoB (g/l)	Before intervention	0.84	0.93
	After intervention	0.84	0.86

Niacin, the coenzyme of about 200 dehydrogenases involved in glycolysis and fatty acids β–oxidation, plays critical roles in lipid metabolism. Pharmaceutical doses of nicotinic acid are used to treat hypercholesterolemia through its effects in lowing serum cholesterol, serum triglycerides, LDL and increasing HDLs.  The effects of LPL polymorphism and niacin intake on the prevalence of metabolic syndrome (MetSyn) were investigated in 548 Koreans (MetSyn: 278, controls: 270). The P+/P+ genotype showed significantly lower levels of HDL and LPL mass and a higher level of TG than the P-/P- genotype. The allele distribution was similar in the MetSyn group and controls. But when niacin intake was considered in the analysis, the P+/P+ genotype had a greatly increased risk (odd ratio 2.39) for MetSyn when the niacin intake level was lower ( 14.82 mg/day). However, at the optimal levels of niacin intake (14.83–17.80 mg/day), the risk for MetSyn was reduced dramatically for the P+/P+ genotype (odd ratio 0.34). A higher than optimal niacin intake ( 17.81 mg/day) diminished the benefit and increased the risk for MetSyn to about 2-fold of that at the optimal niacin intake (odd ratio 0.71). In contrast, niacin intake levels does not affect the P- allele carriers as much (Table 6). These data indicate that optimal levels of niacin intake effectively decreased MetSyn prevalence in the P+P+ mutant group (Shin et al, 2012).

Table 6. Interactions between LPL Pvu II genotypes and niacin intake on the risks for metabolic syndrome (cited from Shin et al, 2012)

LPL Pvu II genotype	Niacin intake (mg/day)	Controls (%)	MetSyn (%)	OR
P-/P- & P-/P+	≤14.82	20.5	17.1	1.00
	14.83 to 17.80	16.5	20	1.08
	≥17.81	16.5	20.7	1.07
P+/P+	≤14.82	13.4	21.4	2.39
	14.83 to 17.80	18.1	9	0.34
	≥17.81	15	15	0.71

Interaction with APOE polymorphisms

The biological effect of APOE polymorphism on lipid metabolism was partially due it its modulation of LPL activity as described in the Apo E and Cholesterol Management review.  Consistently, both the LPL Hind III and S447X polymorphisms interact with the APOE polymorphisms in determining HDL concentrations and TG levels. In general population, the APOE4 allele carriers have lower HDL levels than E2 or E3 individuals. However, a study in a Caucasian population found that APOE4 allele carriers bearing the LPL Hind III H- allele or 447X allele had higher HDL levels than the corresponding E2 or E3 carriers. It seemed that the HDL levels in different APOE genotypes had opposite effects by interacting with LPL Hind III and S447X polymorphisms.  In the same study population, E4 carriers bearing the Hind III H+/H+ or X447S SS genotypes had lower HDL levels than the corresponding E2 or E3 carriers (Fig. 3). The similar effect of APOE and LPL interaction was observed on triglycerides levels, although the effect did not reach statistical significant (Corella et al, 2002).

Figure 3. Interaction between APOE polymorphism and LPL gene variants on HDL-C levels in Caucasians. Mean HDL-C levels differed statistically by the Hind III polymorphism (A) and  the LPL-S447X polymorphism (B) in carriers of the E4 and E3 alleles but not in the E2 carriers (cited from Corella et al, 2002).

Interestingly, tobacco smoking added another layer of interaction between the LPL and the APOE polymorphisms. The effect of the interaction between the LPL Hind III and APOE polymorphisms was increased in non-smokers (Fig. 4A) while abolished in smokers (Fig. 4B) in terms of the effect on HDL levels. Furthermore, the interaction between LPL Hind III and APOE polymorphisms on TG concentrations, while not significant without considering smoking, now became statistically significant in nonsmokers (Corella et al, 2002).

Figure 4. Interaction of tobacco smoking (A: Non-smokers. B: Smokers) on the effects of HDL levels via the interaction between LPL Hind III and APOE polymorphisms (cited from Corella et al, 2002).

Lifestyle and Exercise response

In a study of lifestyle and LPL Hind III polymorphism interaction, 520 Spanish men were divided into two groups according to the median value of daily energy expenditure (291 kcal/day). The group with less than median value is defined as the sedative group and more than the median value as the active group. As expected, subjects in the sedative group had lower HDL and high TG levels when compared to that in the active group. This trend was not affected by Hind III genotypes. However, when smoking was considered, a statistically significant interaction between LPL genotype and physical activity was unmasked. No statistically significant differences were observed in lipid levels of active or sedentary non-smokers between H– carriers and H+H+ homozygotes. In smokers, sedentary H+H+ homozygotes showed significantly higher TG and lower HDL levels than sedentary H– carriers. Among all subgroups, sedentary smokers with the H+H+ genotype had the most adverse lipid profile, followed by a considerably less adverse profile in physically active H+H+ smokers. These findings suggest that adverse environment such as smoking and a sedative lifestyle exacerbate the deleterious effect on lipid profile in the H+H+ genotype (Sentí et al, 2001). Consistently, the improvement of blood pressure and serum lipid profiles was found much greater in H+/H+ genotypes after physical exercise (Hagberg et al, 1999).

In a study involving 146 British Army recruits who underwent a 10-week mixed upper-body strength and lower-body endurance exercises, it was shown that carriers of the X447 allele of the S447X polymorphism had less left ventricular growth than S447 homozygotes (SS, 5.8±0.7% vs. SX, 2.2±1.5%) and a decrease in systolic blood pressure comparing to a increase in SS genotype (ΔSBP: SS, 1.9± 1.3 mmHg; SX, −5.7±2.2 mmHg). While left ventricular growth is a cardiac response to increased workload in physiological to exercise, prolonged left ventricular growth may become pathophysiological and is associated with increased cardiovascular morbidity and mortality. It is known that the adult heart relies predominantly on fatty acids for energy generation, and defects in fatty acids catabolism lead to dramatic left ventricular growth in early age. Therefore, too much exercise may not serve the SS genotype of LPL S447X as well (Flavell et al, 2006).

Medicine response

The influence of the S447X polymorphism on the response to the TZD (thiazolidinedione) insulin sensitizer pioglitazone was investigated in 113 Chinese type 2 diabetes patients. After 30 mg daily pioglitazone treatment for 10 weeks, the SS genotype responded much better than the X allele carriers as measured by relative reduction in fasting blood glucose (FBG). Responder rate of more than 10% FBG reduction was significantly higher in the SS genotype group (84%) than the X carrying group (60%). And the average FBG reduction magnitude of was greater in the SS genotype group (11 to 8.2 mmol/l) than in the X allele carriers group (10.9 to 8.6 mmol/l). Moreover, pioglitazone treatment had significantly more beneficial effects on serum lipid profile and blood pressure in S447S genotype carriers. Therefore, the S allele of the S447X polymorphism renders carriers a greater response to pioglitazone treatment than the X allele (Wang et al, 2007).

Molecular Evolution

As mentioned earlier, the Hind III RFLP and S447X are in strong linkage disequilibrium (Table 3).  The lack of H+X447 haplotype suggests the X477 allele emerged later from the H- allele carriers.  The European Atherosclerosis Research Study (EARS) reported that the H-447X haplotype was associated with lower TG level and lower risk for myocardial infarction (MI). Interestingly, the distribution of this haplotype demonstrated a gradual increase from north to south in five regions of Europe (14 countries) involved in the EARS (Table 7).  This gradient mirrors the gradient of cardiovascular diseases prevalence in Europe, suggesting the possible contributing factor of the interaction between this haplotype and dietary intake (Humphries et al, 1998).

Table 7. LPL haplotype frequency in the five European regions (derived from Humphries et al, 1998)

Region	H+S447	H-S447	H-X447
Finland	0.7	0.181	0.119
UK	0.75	0.16	0.09
North	0.718	0.189	0.093
Middle	0.657	0.211	0.132
South	0.62	0.237	0.143

Conclusions

Three common LPL gene polymorphisms S447X, Hind III, and Pvu II play important role in blood TG and HDL level modulation in response to dietary, lifestyle, exercise and medicine.  Overall the minor alleles of all three polymorphisms have favorable effects on TG and HDL. The major alleles are the risk factors for higher TG and lower HDL related cardiovascular diseases in modern Western life style. People carrying homozygous major allele genotypes should take extra precaution in calorie control, avoid high-saturated-fat diet, take adequate amount of niacin, live an active lifestyle, avoiding excess exercise and smoking to stay healthy.

References

Chang YT, Chang MC, Su TC, Liang PC, Su YN, Kuo CH, Wei SC, Wong JM. 2009. Lipoprotein lipase mutation S447X associated with pancreatic calcification and steatorrhea in hyperlipidemic pancreatitis. J Clin Gastroenterol. 43(6):591-6. PMID:19034041

Corella D, Guillén M, Sáiz C, Portolés O, Sabater A, Folch J, Ordovas JM. 2002. Associations of LPL and APOC3 gene polymorphisms on plasma lipids in a Mediterranean population: interaction with tobacco smoking and the APOE locus. J Lipid Res. 2002 Mar;43(3):416-27. PMID:11893778

Flavell DM, Wootton PT, Myerson SG, World MJ, Pennell DJ, Humphries SE, Talmud PJ, Montgomery HE. 2006. Variation in the lipoprotein lipase gene influences exercise-induced left ventricular growth. J Mol Med (Berl). 84(2):126-31. PMID:16416313

Friedlander Y, Leitersdorf E, Vecsler R, Funke H, Kark J. 2000. The contribution of candidate genes to the response of plasma lipids and lipoproteins to dietary challenge. Atherosclerosis. 2000 Sep;152(1):239-48. PMID:10996360

Goodarzi MO, Guo X, Taylor KD, Quiñones MJ, Saad MF, Yang H, Hsueh WA, Rotter JI. 2004. Lipoprotein lipase is a gene for insulin resistance in Mexican Americans. Diabetes. 53(1):214-20. PMID:14693718

Hagberg JM, Ferrell RE, Dengel DR, Wilund KR.1999. Exercise training-induced blood pressure and plasma lipid improvements in hypertensives may be genotype dependent. Hypertension. 34(1):18-23.PMID:10406818

Huang X, Gong R, Lin J, Li R, Xiao L, Duan W, Fang D. 2011. Effects of lipoprotein lipase gene variations, a high-carbohydrate low-fat diet, and gender on serum lipid profiles in healthy Chinese Han youth. Biosci Trends. 5(5):198-204. PMID: 22101375

Humphries SE, Talmud PJ, Cox C, Sutherland W, Mann J. 1996. Genetic factors affecting the consistency and magnitude of changes in plasma cholesterol in response to dietary challenge. QJM. 89(9):671-80. PMID: 8917741

Humphries SE, Nicaud V, Margalef J, Tiret L, Talmud PJ. 1998. Lipoprotein lipase gene variation is associated with a paternal history of premature coronary artery disease and fasting and postprandial plasma triglycerides: the European Atherosclerosis Research Study (EARS). Arterioscler Thromb Vasc Biol. 18(4):526-34. PMID:9555857

Jemaa R, Tuzet S, Betoulle D, Apfelbaum M, Fumeron F. 1997. Hind III polymorphism of the lipoprotein lipase gene and plasma lipid response to low calorie diet. Int J Obes Relat Metab Disord. 21(4):280-3. PMID:9130024

Johansen CT, Kathiresan S, Hegele RA. 2011. Genetic determinants of plasma triglycerides. J Lipid Res. 2011 Feb;52(2):189-206. PMID: 21041806

Lamon-Fava S, Asztalos BF, Howard TD, Reboussin DM, Horvath KV, Schaefer EJ, Herrington DM. 2010. Association of polymorphisms in genes involved in lipoprotein metabolism with plasma concentrations of remnant lipoproteins and HDL subpopulations before and after hormone therapy in postmenopausal women. Clin Endocrinol (Oxf). 72(2):169-75. PMID: 19489872

Narita S, Tsuchiya N, Wang L, Matsuura S, Ohyama C, Satoh S, Sato K, Ogawa O, Habuchi T, Kato T. 2004. Association of lipoprotein lipase gene polymorphism with risk of prostate cancer in a Japanese population. Int J Cancer. 2004 Dec 10;112(5):872-6. PMID:15386377

Nettleton JA, Steffen LM, Ballantyne CM, Boerwinkle E, Folsom AR. 2007. Associations between HDL-cholesterol and polymorphisms in hepatic lipase and lipoprotein lipase genes are modified by dietary fat intake in African American and White adults. Atherosclerosis. 194(2):e131-40. PMID:17157861

Ordovas JM. 1999. The genetics of serum lipid responsiveness to dietary interventions. Proc Nutr Soc. 1999 Feb;58(1):171-87. PMID: 10343355

Qi Y, Liu J, Wang W, Wang M, Sun JY, Liu J, Li Y, Wu ZS, Zhao D. 2011. The HindIII polymorphism in the lipoprotein lipase gene predicts type 2 diabetes risk among Chinese adults. Clin Chim Acta. 412(13-14):1229-33. PMID: 21419757

Rip J, Nierman MC, Ross CJ, Jukema JW, Hayden MR, Kastelein JJ, Stroes ES, Kuivenhoven JA. 2006. Lipoprotein lipase S447X: a naturally occurring gain-of-function mutation. Arterioscler Thromb Vasc Biol. 26(6):1236-45. PMID:16574898

Sagoo GS, Tatt I, Salanti G, Butterworth AS, Sarwar N, van Maarle M, Jukema JW, Wiman B, Kastelein JJ, Bennet AM, de Faire U, Danesh J, Higgins JP. 2008. Seven lipoprotein lipase gene polymorphisms, lipid fractions, and coronary disease: a HuGE association review and meta-analysis. Am J Epidemiol. 168(11):1233-46. PMID:18922999

Sentí M, Elosua R, Tomás M, Sala J, Masiá R, Ordovás JM, Shen H, Marrugat J. 2001. Physical activity modulates the combined effect of a common variant of the lipoprotein lipase gene and smoking on serum triglyceride levels and high-density lipoprotein cholesterol in men. Hum Genet. 109(4):385-92. PMID:11702219

Shin E, Park NY, Jang Y, Oh H, Jeong J, Lim Y, Lee M. 2012. The association of lipoprotein lipase PvuII polymorphism and niacin intake in the prevalence of metabolic syndrome: a KMSRI-Seoul study. Genes Nutr. 7(2):331-41. PMID: 22038562

Wang G, Wang X, Zhang Q, Ma Z. 2007. Response to pioglitazone treatment is associated with the lipoprotein lipase S447X variant in subjects with type 2 diabetes mellitus. Int J Clin Pract. 61(4):552-7. PMID:17394430

Wang H, Eckel RH. 2009. Lipoprotein lipase: from gene to obesity. Am J Physiol Endocrinol Metab. 297(2):E271-88. PMID:19318514