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Liver Fat and Insulin Resistance Are Independently Associated with the –514C>T Polymorphism of the Hepatic Lipase Gene

Department of Internal Medicine, Division of Endocrinology, Metabolism, and Pathobiochemistry (N.S., S.S., F.M., H.-U.H., A.F.), and Section on Experimental Radiology (J.M., F.S., C.D.C.), University of Tübingen, D-72076 Tübingen, Germany; and Department of Internal Medicine (M.S.), University of Leipzig, 100920 Leipzig, Germany

Address all correspondence and requests for reprints to: Norbert Stefan, M.D., Department of Internal Medicine, Division of Endocrinology, Metabolism, and Pathobiochemistry, Otfried-Müller-Strasse 10, D-72076 Tübingen, Germany. E-mail: norbert.stefan{at}med.uni-tuebingen.de.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: Liver fat predicts insulin resistance in humans. So far, there is not much information on genetic determinants of liver fat. Hepatic lipase is a liver-specific enzyme that regulates lipid metabolism.

Objective: First, our object was to investigate whether the functional –514C>T polymorphism of the hepatic lipase gene is associated with liver fat content and with insulin sensitivity. Second, because this polymorphism displays gene-nutrient interactions, we assessed gene-gene interactions with the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-₂ on liver fat content and insulin sensitivity.

Design and Methods: Cross-sectional data from a total of 1070 nondiabetic subjects were analyzed. Insulin sensitivity was estimated from a 75-g oral glucose tolerance test. A subgroup of 115 subjects underwent measurements of liver fat.

Results: The –514C>T polymorphism of the hepatic lipase gene was associated with higher liver fat content (P = 0.005) and lower insulin sensitivity (P = 0.02), both after adjustment for age, gender, and percentage of body fat. This was independent of serum adiponectin concentrations (P = 0.01 and 0.03). However, there was an interaction of the –514C>T polymorphism with the Pro12Ala variant on liver fat (P = 0.09) and insulin sensitivity (P = 0.01). Subjects carrying the –514C>T polymorphism had higher liver fat content and were insulin resistant only before the background of the Pro/Pro genotype of the Pro12Ala polymorphism.

Conclusions: The –514C>T polymorphism of the hepatic lipase gene is associated with higher liver fat content and lower whole-body insulin sensitivity. However, these effects are modulated by the common Pro12Ala polymorphism in peroxisome proliferator-activated receptor-₂. These findings may be relevant for intervention strategies to prevent increase in liver fat content and insulin resistance.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
INSULIN RESISTANCE IS an important factor in the development of type 2 diabetes and is frequently associated with dyslipidemia and atherosclerosis (1). Multiple mechanisms are thought to contribute to its pathogenesis. Liver fat was found to be a determinant of insulin resistance in humans (2, 3, 4). Moreover, the role of ectopic fat disposition, particularly in liver, is considered a major factor for the development of type 2 diabetes (5, 6). Thus, increase in liver fat may represent a mechanism linking insulin resistance and type 2 diabetes.

Hepatic lipase is a liver-specific enzyme that controls hepatic lipoprotein metabolism (7, 8, 9). It catalyzes hydrolysis of triglycerides (TGs) and phospholipids in all major classes of lipoproteins. The activity of hepatic lipase increases with increased visceral fat content (10). Whether hepatic lipase also regulates liver fat content is unknown. The –514C>T polymorphism of the hepatic lipase gene is associated with decreased plasma hepatic lipase activity, increased high-density lipoprotein (HDL)-cholesterol, and decreased cardiovascular disease in most (11, 12, 13, 14, 15, 16) but not in all (17) reports. In addition, this polymorphism was found to be associated with higher visceral adipose tissue, and increase in visceral fat attenuated the impact of the polymorphism on HDL-cholesterol (18). Thus, visceral adiposity may explain the different associations of the polymorphism with metabolic characteristics among populations. Another underlying mechanism may be gene-environment and/or gene-gene interaction. This variant was shown to interact with dietary fats on plasma lipid profiles in the Framingham Study (19) and in a multiethnic Asian population (20). Therefore, a specific diet in different populations may modulate the impact of the polymorphism on lipid metabolism.

Data on insulin sensitivity, glucose tolerance, and conversion from impaired glucose tolerance (IGT) to type 2 diabetes were also not consistent among studies. The –250G>A substitution in the promoter of the hepatic lipase gene that is in almost complete linkage disequilibrium with the –514C>T variant was associated with increased insulin resistance (21) and reduced glucose tolerance (22). We found that this polymorphism was associated with elevated fasting insulin concentrations (23). However, subjects carrying the –250 A allele had a lower rate of conversion to type 2 diabetes compared with carriers of the –250 G allele in the Finnish Diabetes Prevention Study (24). Explanations for these differences also include that the polymorphism may behave in a protective manner specifically in individuals with IGT as discussed by Shuldiner et al. (25). Moreover, gene-environment and/or gene-gene interactions in the different populations may play a role.

The common Pro12Ala polymorphism of the peroxisome proliferator-activated receptor (PPAR)-₂ is an important candidate in the pathogenesis of type 2 diabetes. Moreover, it plays a crucial role in lipid metabolism and displayed gene-gene and gene-nutrient interactions (26). Thus, the mutation in this master transcription factor may display a gene-gene interaction with the –514C>T polymorphism.

We hypothesized that the –514C>T polymorphisms of the hepatic lipase gene modulates liver fat content and, thus, confers to insulin resistance. Therefore, we investigated first whether this polymorphism was associated with liver fat content and with insulin sensitivity in nondiabetic subjects. Second, we investigated whether the –514C>T polymorphisms interact with the Pro12Ala polymorphism of PPAR₂ on liver fat content and insulin sensitivity.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

We analyzed cross-sectional data from a total of 1070 normal and impaired glucose-tolerant subjects who participated in the ongoing Tübingen Family Study for type 2 diabetes. In the present analyses, only 0.1% of subjects were related to each other. Liver fat content was measured in a subgroup of 115 individuals. The participants did not take any medication known to affect glucose tolerance or insulin sensitivity. Tests were done at 0700 h after an overnight fast of 12 h. Informed written consent was obtained from all participants, and the local medical ethics committee had approved the protocol.

Body composition and body fat distribution

Body composition was measured by bioelectrical impedance as percentage body fat. Body mass index (BMI) was calculated as weight divided by the square of height (kilograms per square meter). Waist and hip circumferences were measured in the supine position, and waist-to-hip ratio was calculated as an index of body fat distribution.

Oral glucose tolerance test (OGTT)

All subjects underwent a 75-g oral OGTT, and venous blood samples were obtained at 0, 30, 60, 90, and 120 min for determination of plasma glucose, insulin, and C peptide. Glucose tolerance was determined according to the 1997 World Health Organization diagnostic criteria (27). Insulin sensitivity was calculated from glucose and insulin values during the OGTT as proposed by Matsuda and DeFronzo (28).

Liver fat content

Liver fat content was determined by localized proton magnetic resonance spectroscopy using a 1.5 T whole-body imager (Magnetom Sonata, Siemens Medical Solutions, Erlangen, Germany). For volume selection, a single-voxel STEAM technique was applied (replication time = 4 sec, echo time = 10 msec, 32 acquisitions), and a voxel of 3 x 3 x 2 cm³ was placed in the posterior part of the seventh segment of the liver. Subjects were asked to breathe within the replication time interval and to be in expiration during data acquisition. The liver fat content was quantitatively assessed by analyzing the signal integrals of methylene and methyl resonances (between 0.7–1.5 ppm) using the liver water signal integral at 4.8 ppm as internal reference.

Analytical procedures

Blood glucose was determined using a bedside glucose analyzer (glucose-oxidase method, YSI Inc., Yellow Springs, OH). Plasma insulin was determined by microparticle enzyme immunoassay (Abbott Laboratories, Tokyo, Japan). Serum and plasma samples were frozen immediately and stored at –20 C for determination of adiponectin by RIA (LINCO Research, St. Charles, MO) and free fatty acids (FFAs), with an enzymatic method (WAKO Chemicals, Neuss, Germany). Lipoprotein concentrations were measured with a standard colorimetric method using the Roche/Hitachi analyzer (Roche Diagnostics, Mannheim, Germany). Apolipoprotein B (apoB) was measured in serum using a Behring nephelometer and commercially available antibodies (Behringwerke, Marburg, Germany).

Genotyping

Genotyping of the –514C>T polymorphism of the hepatic lipase gene and of the Pro12Ala polymorphism of the PPAR₂ gene was done as previously described (16, 29).

Statistical analyses

Unless otherwise stated, data are given as mean ± SE. Statistical comparison between genotype groups was performed by ANOVA using logarithmically transformed data (for nonnormally distributed parameters). To adjust the effects of relevant covariates (age, sex, percentage of body fat), multivariate linear regression analyses were performed. The association of the polymorphism with anthropometrics and metabolic characteristics was tested in an additive and in a dominant model. The statistical software package JMP (SAS Institute, Inc., Cary, NC) and SPSS version 10.0 software (SPSS, Inc., Chicago, IL) was used.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The frequency of the rare allele (T) of the –514C>T polymorphism of the hepatic lipase gene was approximately 0.19 in our population. The genotype distribution was in Hardy-Weinberg equilibrium (P = 0.48; ² test). Data on associations of this polymorphism with anthropometrics and metabolic characteristics were previously reported in a subgroup (n = 535) (21).

As reported in Table 1, carriers of the –514C>T allele had higher BMI and percentage of body fat compared with noncarriers of this allele. There was no association between genotype and body fat distribution and fasting and 2-h glycemia (except for a small difference in 2-h glycemia in the additive model) before and after adjustment for age, gender, and percentage of body fat.

Liver fat content was negatively associated with insulin sensitivity (r = –0.55; P < 0.0001), serum adiponectin concentrations (r = –0.24; P = 0.009), and serum HDL levels (r = –0.29, P = 0.003). Liver fat content was positively associated with serum low-density lipoprotein (LDL) and TG levels (r = 0.22; P = 0.02; r = 0.37, P < 0.0001) and with serum apoB levels (r = 0.31; P = 0.009) independent of age, gender, and percentage of body fat. Liver fat content was higher in subjects with the polymorphism compared with those who were homozygous for the C allele (P = 0.01; Table 2 and Fig. 1A). This was independent of age, gender, and percentage of body fat (P = 0.005) and, in addition, of adiponectin concentrations (P = 0.01). Additional adjustment for fasting and 2-h FFA also did not affect this relationship (all P < 0.007). The association between liver fat content and the genotype was also similar when subjects who were NGT (n = 80; P = 0.04) and individuals who were IGT (n = 36; P = 0.05, dominant models) were analyzed separately. The polymorphism was also associated with higher apoB levels [additive model, 90 ± 2 mg/dl (CC), 99 ± 4 mg/dl (CT), 105 ± 13 mg/dl (TT), P = 0.08; and dominant model, P = 0.03].

View larger version (19K): [in this window] [in a new window]   FIG. 1. Associations of the –514C>T polymorphism of the hepatic lipase gene with liver fat content. Carriers of the T allele (X/T) were compared with subjects homozygous for the C allele after adjustment for age, gender, and percentage of body fat (A). Associations of the –514C>T polymorphism of the hepatic lipase gene with liver fat content on the background of the Pro12Ala polymorphism of the PPAR2 gene. Subjects carrying the T allele had a higher liver fat content only when they concomitantly had the Pro/Pro genotype in PPAR2 (B).

Subjects homozygous and heterozygous for the Ala-encoding allele (X/Ala) did not differ from those with Pro/Pro in insulin sensitivity (P = 0.31) or liver fat (P = 0.43). However, the association of the –514C>T polymorphism of the hepatic lipase gene with insulin sensitivity and liver fat content differed on the background of the Pro12Ala polymorphism. Subjects carrying the –514C>T polymorphism were insulin resistant or had increased liver fat content only when the Pro/Pro genotype of the Pro12Ala polymorphism was present [P for interaction = 0.01 (insulin sensitivity) and P for interaction = 0.09 (liver fat content); Fig. 1B].

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Liver fat emerges as an important determinant of glucose tolerance. Although its associations with insulin sensitivity and particularly insulin sensitivity of the liver to suppress endogenous glucose production are well documented (3, 4, 30, 31, 32), there is a lack of information on genetic determinants of liver fat. This may be due to the relatively elaborate techniques to precisely quantify liver fat in humans. Magnetic resonance spectroscopy is the best noninvasive method to date (6). With this technique, we investigated whether genetic variants of the hepatic lipase gene may represent candidates explaining the variability in liver fat seen in our population. We chose this gene because it plays an important role in lipid metabolism. Particularly the promoter polymorphisms in the hepatic lipase gene were found to be associated with plasma lipid profile and insulin sensitivity (11, 12, 13, 14, 15, 16, 21, 22, 23, 24). Among them, the –514C>T polymorphism was also shown to be functional (14).

We found that this genetic variant predicted liver fat content in our study. This was independent of other factors such as age, gender, and percentage of body fat.

Most importantly, the polymorphism was associated with liver fat content independent of plasma adiponectin concentrations. In other studies, serum adiponectin was found to be a determinant of liver fat (30, 33). This is in agreement with animal and in vitro data showing that adiponectin increases lipid oxidation and, thus, decreases liver fat content (34, 35). This was interpreted as an important mechanism of adiponectin action to increase hepatic insulin sensitivity and glucose tolerance. Because we found that the –514C>T polymorphism in the hepatic lipase gene was associated with liver fat content independent of this adipokine, the role of hepatic lipase in human lipid metabolism is further substantiated.

Another important player in the regulation of liver fat content is flux of FFA from visceral fat to the liver (36). To account for a potential effect of this polymorphism on liver fat content by regulation of serum FFA, we performed additional adjustment for fasting and 2-h FFA. This adjustment did not affect the association of the polymorphism with liver fat content. This supports the hypothesis that the –514C>T polymorphism may not affect liver fat through regulation of serum FFA.

It is of note that in several studies (11, 12, 13, 14, 15, 16, 23), the T allele of the –514C>T polymorphism was found to be associated with higher HDL cholesterol levels in serum. Liver fat content is negatively associated with serum HDL cholesterol levels and positively with TGs, total cholesterol, and LDL cholesterol (33). Therefore, it may seem paradoxical that the T allele was associated with higher liver fat content.

Explanations for this may, first, include differences in fatty liver-induced expression of enzymes regulating lipoprotein metabolism. Although there are excellent data in animals showing an association of fatty liver with altered expression patterns of enzymes involved in lipoprotein metabolism such as PPAR (37), there is less information in humans. Gene-gene interactions of the –514C>T polymorphism with these master transcription factors may also play a role here. Second, low hepatic lipase activity in carriers of the T allele may have separate and stronger effects on liver fat content than on HDL levels. In our analysis in the subgroup of individuals with measurements of liver fat content, the polymorphism was not associated with HDL levels. Moreover, patients with the rare syndrome of hepatic lipase deficiency had high serum total and LDL-cholesterol and TGs but normal HDL-cholesterol (38).

It is of interest that the –514C>T polymorphism in our study was associated with high liver fat content and insulin resistance that is commonly associated with increased risk for atherosclerosis (39). However, the T allele was found to be associated with higher HDL levels and large, buoyant, less atherogenic LDL levels (11), and one may expect that the polymorphism is associated with decreased insulin resistance. In a recent study, it was hypothesized that the mutation decreases the potency of the hepatic lipase for the reverse cholesterol transport from the periphery, here the vessel wall, to the liver (17). It was further suggested that this effect was more important for atherosclerosis than LDL particle size and total HDL levels. Indeed, the T allele was associated with increased risk for coronary artery disease (17).

Further support for our findings that the –514C>T polymorphism may affect liver fat content derives from studies on apoB metabolism. Hepatic lipase overexpression in mice resulted in a decrease in apoB-containing lipoproteins in serum, whereas HDL concentrations were minimally affected (40). Conversely, hepatic lipase-deficient patients were found to have increased levels of apoB (38). It was suggested that hepatic lipase activity was required for apoB uptake by the liver (8). In our study, the T allele was associated with higher apoB concentrations in plasma, suggesting a lower uptake of apoB. As previously shown (41, 42) by another group, also in our study, high apoB concentrations were found to be associated with high liver fat content.

Studies investigating associations of the –514C>T polymorphism with lipid metabolism and insulin sensitivity also reported inconsistent findings (21, 22, 23, 24). Because this polymorphism was shown to have gene-nutrient interactions, we further hypothesized that a gene-gene interaction with the Pro12Ala polymorphism in PPAR₂ may exist. This common variant also displayed gene-nutrient interactions (43) and gene-environment interactions (44). Therefore, different results on associations of the –514C>T polymorphism in the hepatic lipase gene with lipid and glucose metabolism may be explained by different occurrence of both variants in the populations studied. Indeed, there was an interaction of both genetic variants, indicating that the effect of the –514C>T polymorphism of the hepatic lipase gene to increase liver fat content was attenuated under the Pro12Ala background.

To corroborate the hypothesis of an interaction between both polymorphisms, we analyzed our large database where insulin sensitivity was estimated in 1070 nondiabetic subjects in the Tübingen Family Study. The –514C>T polymorphism, but not the Pro12Ala polymorphism, was associated with insulin resistance in our study including mostly young and lean subjects. This is consistent with previous reports on associations of both variants with insulin sensitivity in our population (23, 29). However, as hypothesized, we found that the –514C>T polymorphism of the hepatic lipase gene was associated with insulin resistance only under the Pro/Pro genotype in PPAR₂. It remains unexplained by which mechanism this happens. It is possible that the dietary fat intake plays a role. Both polymorphisms were found to interact with fat in the diet. The –514C>T polymorphism of the hepatic lipase gene was found to be associated with higher cardiovascular risk only under high intake of saturated fat (19). The Pro12Ala polymorphism in PPAR₂ was associated with decreased BMI when saturated fat intake was low (43). Therefore, one may hypothesize that unsaturated fats that were found to be strong ligands for PPAR (45) may activate this master transcription factor mostly before the Pro12Ala background. Thus, the beneficial effects of the Pro12Ala polymorphism on lipid metabolism (26) may attenuate the negative effect of the –514C>T polymorphism of the hepatic lipase gene on liver fat and insulin sensitivity.

In conclusion, the –514C>T polymorphism of the hepatic lipase gene increases liver fat content and reduces whole-body insulin sensitivity. However, this effect is modulated by the common Pro12Ala polymorphisms in PPAR₂. These findings may represent new strategies to prevent type 2 diabetes. Intervention including diet, physical activity, and possibly pharmacology may target mainly subjects with the –514C>T polymorphism of the hepatic lipase gene. This may be important particularly for subjects with hepatic insulin resistance. Also, intervention may be even more efficient on the background of the Pro/Pro genotype of the PPAR₂ gene. This needs to be proven in epidemiological studies.

	Acknowledgments

 
We thank all the research volunteers for their participation. We gratefully acknowledge the superb technical assistance of Elke Maerker, Anna Teigeler, and Heike Luz. The authors would also like to thank all participants for their cooperation.

	Footnotes

 
This work was supported by Grant KFO 114/1 from the Deutsche Forschungsgemeinschaft and the European Community’s FP6 EUGENE2 (LSHM-CT-2004-512013).

First Published Online April 26, 2005

Abbreviations: apoB, Apolipoprotein B; BMI, body mass index; FFA, free fatty acid(s); HDL, high-density lipoprotein; IGT, impaired glucose tolerance; LDL, low-density lipoprotein; NGT, normal glucose tolerant; OGTT, oral glucose tolerance test; PPAR₂, peroxisome proliferator-activated receptor ₂; TG, triglyceride.

Received December 17, 2004.

Accepted April 15, 2005.

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