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Originally published In Press as doi:10.1194/jlr.M800135-JLR200 on August 27, 2008

Papers In Press, published online ahead of print January 1, 2009
J. Lipid Res., doi:10.1194/jlr.M800135-JLR200
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Journal of Lipid Research, Vol. 50, 41-46, January 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Identification of SMEK2 as a candidate gene for regulation of responsiveness to dietary cholesterol in ratsboxs

Makoto Asahina, Waka Haruyama, Yasuhiro Ichida, Mai Sakamoto, Masao Sato and Katsumi Imaizumi1

Laboratory of Nutrition Chemistry, Faculty of Agriculture, Kyushu University, Fukuoka 812-8581, Japan

boxs The online version of this article (available at http://www.jlr.org) contains supplementary Materials and Methods. Back

Published, JLR Papers in Press, August 27, 2008.

This study was supported by the National Bio Resource Project for the Rat in Japan. This study was supported in part by Grants-in-aid for Scientific Research (B2; 16380090 and B; 18380083).

1 To whom correspondence should be addressed. e-mail: imaizumi{at}agr.kyushu-u.ac.jp


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
We have previously mapped a diet-induced hypercholesterolemia locus (Dihc2) to chromosome 14 in the F2 generation cross of high-responsive exogenous hypercholesterolemia rats and low-responsive BN rats. To identify a causal gene within this locus, we constructed interval-specific congenic lines and carried out expression and sequencing analyses. Here we narrowed Dihc2 to a region including 33 genes and predicted transcripts and identified RGD1309450_predicted, a homologous gene of SMEK2, as a strong candidate for responsiveness to dietary cholesterol. Our finding provides new insights into the pathway underlying the individual responsiveness to dietary cholesterol in vivo.

Supplementary key words ExHC rat • diet-induced hypercholesterolemia • congenic strains • interval-specific congenic lines


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Coronary heart disease is a leading cause of mortality in most industrialized countries. Epidemiological studies support that hypercholesterolemia is a major risk factor for coronary heart disease (1). The concentration of total cholesterol in serum is a quantitative and continuous trait that is controlled by complex systems involving environmental and polygenic factors and their interactions. Dietary cholesterol is an environmental factor that raises the total concentration of serum cholesterol in humans and animals (2, 3). However, individuals vary widely in the response to dietary cholesterol, implying individual genetic variability (4). Some genes whose polymorphisms influence the response to dietary cholesterol have already been reported in humans (5). In addition, novel quantitative trait loci (QTLs) for the response to dietary cholesterol have been identified. A genetic study of the stroke-prone spontaneously hypertensive rat, which showed an exaggerated response to a high-fat, high-cholesterol diet, showed QTLs for postdietary cholesterol levels on rat chromosomes 7, 15, and 16 (6). The genetic locus for diet-dependent hypercholesterolemia in the New Zealand obese mouse was also identified on distal mouse chromosome 5 (7). QTL analyses of an intercross of CAST/Ei and DBA/2J mice fed a high-cholesterol diet identified novel a QTL for total cholesterol on mouse chromosome 9 (8). However, these novel genetic loci have not been elucidated in the identification of causal genes.

Exogenously hypercholesterolemia (ExHC) rats generated from SD rats showed a 3-fold higher serum total cholesterol level than SD rats when fed a 1% cholesterol-containing diet for 2 weeks (9, 10). Thus, the ExHC rat is an appropriate model animal for evaluating the effects of dietary cholesterol on serum total cholesterol levels. To identify factors associated with the response to dietary cholesterol, we carried out QTL analyses using high-responsive ExHC rats, low-responsive BN rats, and (ExHC x BN)F2 progeny fed a diet containing 1% cholesterol (11). We mapped diet-induced hypercholesterolemia QTLs to rat chromosomes 5 and 14, and labeled them as diet-induced hypercholesterolemia1 (Dihc1) and Dihc2 (11).

In the present study, we first constructed an Ex.BN-Dihc2 congenic strain to confirm that Dihc2 is a QTL for diet-induced hypercholesterolemia. Second, we tried to identify more precisely a Dihc2 congenic fragment using interval-specific congenic lines (ISCLs). Third, we carried out expression analyses and sequencing of genes within the localized region for positional cloning or candidate gene cloning of a causal gene underlying Dihc2. Our findings suggest that a strong candidate gene in Dihc2 regulates the response to dietary cholesterol in rats.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
An expanded Materials and Methods section is in the online data supplement.

Inbred strains
BN/Sea (BN), Dahl S/Jr Sea (Dahl), and LEW/Sea (LEW) rats were obtained from KYUDO; ACI/N Slc (ACI), F344/N Slc (F344), and WKY/Izm (WKY/I) rats were from Japan SLC; and WKY/NCrlCrlj (WKY/N) rats were from Japan Charles River. ExHC/Sea (ExHC) rat colonies have been maintained in our institute with brother-sister matings.

The construction of congenic strains and a series of ISCLs
Ex.BN-Dihc2 congenic strains were constructed according to the speed congenic protocol (12). The congenic strains were backcrossed to ExHC rats for the production of rats with recombinant Dihc2 regions, and then recombinant rats were backcrossed to ExHC rats to construct a series of ISCLs.

Diets and phenotypes
Until they reached of 4 weeks of age, animals were maintained as described (11). Subsequently, rats were fed an AIN76-based purified diet containing 1% cholesterol and 10% olive oil for 2 weeks, and then blood, liver, and tail chips were obtained without fasting. Total cholesterol in the serum and triacylglycerol (TG) and cholesterol in the liver were measured as described (10, 11). The number of animals is shown in parentheses in each figure. These experiments were carried out under the guidelines for animal experiments of the Faculty of Agriculture and Graduate Course at Kyushu University and Law No. 105 and Notification No. 6 of the Government of Japan.

Genotyping
Individual DNA was extracted from tail tips and used for genotyping of simple sequence-length polymorphism markers as de scribed (11). The single nucleotide polymorphisms (SNPs) between the ExHC and BN alleles were determined by the direct-sequencing method, and some SNP markers were genotyped in ISCLs by the PCR-restriction fragment-length polymorphism method.

Expression analysis in liver
We utilized two databases, Ensembl and GeneBank, to find known genes and predicted transcripts located in the narrowed Dihc2 region. Then we carried out quantitative real-time PCR to compare mRNA expression between ExHC and BN rats. Actb was used as an internal control gene.

Sequencing
Two to three clones of the coding and upstream regions in ExHC and BN rats were sequenced. Nucleotide differences were confirmed in six inbred rat strains: ACI, Dahl, F344, LEW, WKY/I, and WKY/N.

URLs
Rat Genome Database is available at http://rgd.mcw.edu/, UCSC Genome Bioinformatics Genome Browser at http://genome.ucsc.edu/cgi-bin/hgGateway/, and NCBI Rat Genome Resource at http://www.ncbi.nlm.nih.gov/genome/guide/rat/.

Statistical analysis
The statistical significance of differences between groups was determined using two-sided Student's t-test for comparisons between two groups or a one-way ANOVA with Sheffe's multiple comparisons post-test for comparisons among more than three groups.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Ex.BN-Dihc2 congenic rats are protected against diet-induced hypercholesterolemia
To confirm the effect of the Dihc2 locus on the responsiveness to dietary cholesterol, we constructed an Ex.BN-Dihc2 congenic strain that had the introgressed low-responsive BN allele of Dihc2 on the high-responsive ExHC background genome. Ex.BN-Dihc2 rats showed lower postdietary serum total cholesterol than the background strain (Fig. 1A ). The congenic strain showed lower postdietary serum total cholesterol levels than its noncongenic Ex.Ex homozygous littermates (Fig. 1B). These results reveal that a gene influencing the response to dietary cholesterol is contained within the introgressed interval.


Figure 1
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  		Fig. 1. Ex.BN-Dihc2 congenic rats are protected against diet-induced hypercholesterolemia. Serum cholesterol concentrations in male ExHC, BN, and Ex.BN-Dich2 rats (A) and Ex.BN-Dihc2 (BN/BN) rats and their littermates (Ex/BN and Ex/Ex) (B). The rats were fed a cholesterol-containing diet for 2 weeks. The number of animals is shown in parentheses. The values are means ± SEM. Different letters above the bars indicate a significant difference at P < 0.01.

 
Fine mapping of Dihc2
To narrow the Dihc2 region, a series of ISCLs were constructed by continuous backcrosses of ExHC rats to Ex.BN-Dich2 congenic strains. The congenic strain with the Ex.BN heterozygous allele in Dihc2 had lower postdietary serum total cholesterol levels than did its noncongenic Ex.Ex homozygous littermates (Fig. 1B), indicating the dominance of the BN allele. Phenotypic comparisons between ISCLs with the Ex.BN heterozygous Dihc2 region and their Ex.Ex homozygous littermates in each ISCL were then conducted to determine which introgressed region affects the susceptibility to diet-induced hypercholesterolemia. ISCL1–4 rats showed significant decreases in the postdietary serum cholesterol level when compared with their Ex.Ex littermates, indicating that a causal gene is contained in the 4.1 Mb introgressed region spanning D14Kyu7 and the telomere (Fig. 2 ).


Figure 2
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  		Fig. 2. Fine mapping of Dihc2 using interval-specific congenic lines (ISCLs). ISCLs were compared with their noncongenic littermates for postdietary serum total cholesterol levels. Left: A series of ISCLs, 1–4, were derived from recombinant rats of Ex.BN-Dihc2 congenic strains. White areas show the chromosomal segments homozygous for Ex/Ex alleles, black segments indicate the region heterozygous for Ex/BN alleles, and gray regions indicate the boundary regions where alleles are not determined. The markers and their positions on chromosome 14 are shown at the top of the figure. Right: Postdietary serum cholesterol levels (mean ± SEM) are given for the ISCL1–4 progeny (Ex/BN) and their noncongenic littermates (Ex/Ex). The rats were fed a cholesterol-containing diet for 2 weeks. Asterisks indicate significant differences at P < 0.05.

 
Expression analyses of genes within the localized Dihc2 region
Our previous study suggested that diet-induced hypercholesterolemia in ExHC rats could be attributed to increased secretion of slowly metabolized VLDL enriched in cholesteryl ester (CE) by the liver (10, 13). Therefore, we performed RT-PCR to evaluate the gene expression in the liver. Using public rat genome information, we initially found 33 genes and predicted transcripts located within the 4.1 Mbp region. Then mRNA expression in the liver was confirmed for 27 genes. We compared mRNA expression of these 27 genes between ExHC and BN strains using real-time quantitative PCR. Of these genes, RGD1309450_predicted showed a highly significant difference between the two strains (P = 1.7 x 10–6) (Table 1 ), with BN rats showing 5-fold higher mRNA expression than ExHC rats. To determine whether RGD1309450_predicted transcript levels were influenced by the Dihc2 locus, we examined mRNA expression in the Ex.BN-Dihc2 congenic strain. The congenic strain also exhibited significantly increased mRNA expression of RGD1309450_predicted when compared with the ExHC background strain (Fig. 3 ).


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  		TABLE 1. Expression analyses of genes located within the refined 4.1 Mbp region

 

Figure 3
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  		Fig. 3. Expression analyses of RGD1309450_predicted in ExHC, BN, and Ex.BN-Dihc2 rats. mRNA expression levels were determined by real-time quantitative PCR for each gene and standardized by Actb expression. Rats were fed a cholesterol-containing diet for 2 weeks. The number of animals is shown in parentheses. The values are means ± SEM. Different letters above the bars indicate a significant difference at P < 0.01.

 
Sequencing analyses identified a 10 bp deletion leading to a nonsense mutation in ExHC rats
We sequenced the coding and upstream regulatory regions of RGD1309450_predicted in ExHC and BN rats. Two nucleotide differences in the upstream region and a 10 bp deletion in the coding region at codon 713 in ExHC rats were identified in RGD1309450_predicted (Table 2 , Fig. 4A ). This 10 bp deletion existed in ExHC rats but not in the other seven strains, which are not hyper-responders to dietary cholesterol (Table 2). Two SNPs in the upstream regions were not specific for ExHC rats (Table 2). A homology search showed that rat RGD1309450_predicted is highly conserved with mouse and human SMEK2, exhibiting 98% and 94% similarity, respectively (Fig. 4B). The10 bp deletion led to a nonsense mutation with the creation of a premature stop codon at the 758 position (Fig. 4B).


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  		TABLE 2. Nucleotide differences in rat RGD1309450_predicted among eight inbred strains

 

Figure 4
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  		Fig. 4. Sequencing analyses identified a 10 bp deletion leading to a nonsense mutation in ExHC rats. A: Chromatograms showing the 10 bp deletion. B: The structure of the SMEK2 protein and the position of the stop codon arising from the nonsense mutation. Red areas show the EVH1 domain; green segments show the DUF-625 domain; and blue regions indicate the C-terminal conserved acidic/basic stretch (A/B).

 
Liver lipid analyses in ExHC, BN, and Ex.BN-Dihc2 rats
Previously we showed that ExHC rats had lower liver TG levels than the original strain of ExHC rats, SD rats, which have a lower response to dietary cholesterol than do ExHC rats. We also showed increased formation of CE-rich VLDL in ExHC rats fed a cholesterol-containing diet (10, 13). These results raised the possibility that liver TG levels can be associated with the susceptibility to hypercholesterolemia in ExHC rats (10, 13). Therefore, we tested whether the Dihc2 locus is associated with the regulation of liver TG levels using the Ex.BN-Dich2 congenic strain. ExHC rats showed decreased liver TG levels when compared with BN and Ex.BN-Dihc2 rats (Fig. 5A ). However, there was no difference in cholesterol levels between ExHC and Ex.BN-Dihc2 rats, and their cholesterol levels were lower than those of BN rats. These results indicate that Dihc2 is associated with the regulation of liver TG levels, but not cholesterol levels.


Figure 5
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  		Fig. 5. Liver lipid analyses in ExHC, BN, and Ex.BN-Dihc2 rats. Liver triacylglycerol (A) and cholesterol (B) were measured. Rats were fed a cholesterol-containing diet for 2 weeks. The number of animals is shown in parentheses. The values are means ± SEM. Different letters above the bars indicate a significant difference at P < 0.05.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this study, we identified RGD1309450_predicted as a candidate gene for the Dihc2 locus in rats using ISCLs and expression and sequencing analyses of genes. A homology search showed that rat RGD1309450_predicted is highly homologous to SMEK2 in humans and mice. It is therefore likely that SMEK2 is associated with the high responsiveness to dietary cholesterol in ExHC rats.

Our previous study showed that ExHC rats had decreased liver TG levels and secreted relatively CE-rich VLDL when compared with the SD original strain (10, 13). Liver lipid analyses in ExHC, BN, and Ex.BN-Dich2 rats indicated that the Dihc2 locus including SMEK2 is associated with liver TG levels, but not cholesterol levels (Fig. 5). Although the relative effects of CE versus TG in the regulation of VLDL secretion remain controversial, the size of the intracellular triglyceride pool is known to determine VLDL secretion (14). There is evidence suggesting that 60–70% of VLDL-triglyceride is derived from lipolysis of cytoplasmic triglycerides (14). Thus, we suggest that ExHC rats secrete relatively CE-rich VLDL owing to their low levels of liver TG.

Tsai et al. (15) have shown that MEK1/2 inhibition significantly increases cellular and microsomal TG mass, but not cholesterol mass, in HepG2 cells and thereby induces the secretion of relatively-TG rich VLDL. This finding implies that MEK/ERK signal transduction is associated with TG levels in the liver and regulates VLDL components (15). SMEK2 was originally identified by Mendoza et al. (16) as a suppressor of MEK1 in Dictyostelium using a mek1 mutant by using a second-site suppressor. They described that SMEK regulated some MEK1 effectors in a manner opposite to that of the MEK1/ERK1 pathway, and that SMEK signaling converged on a partially overlapping set of MEK1 effectors (16). These results suggest that SMEK is associated with the regulation of liver TG levels in a manner opposite to that of the MEK/ERK pathway.

In the present study, sequencing analysis detected an ExHC-specific 10 bp deletion that led to a nonsense mutation in SMEK2 in eight inbred rat strains. Premature mRNA may be degraded by nonsense-mediated decay, which is an mRNA surveillance mechanism that detects and selectively degrades mRNA transcripts containing premature termination codons (17). Thus, the ExHC-specific 10 bp deletion in SMEK2 is consistent with the highly decreased mRNA expression of SMEK2 in ExHC rats. In vegetative cells, SMEK localizes to the cell cortex through the EVH1 domain and translocates to the nucleus via a nuclear localization signal at its C terminus basic stretch in response to starvation signals (16). Because the SMEK2 protein lacks the conserved C-terminal basic stretch in ExHC rats (Fig. 4B), SMEK2 may not be translocated into the nucleus, and hence may not function as a mek1 suppressor in ExHC rats. Thus, we suggest that dysfunction and decreased mRNA expression of SMEK2 in ExHC rats led to the decreased TG levels in the liver. This speculation is consistent with the liver TG levels in ExHC, BN, and Ex.BN-Dihc2 rats (Fig. 5). SMEK2 is highly conserved from yeasts to humans, so its MEK suppressor function in Dictyostelium should parallel that in mammalian systems.

Although our approach has successfully identified SMEK2 as a strong candidate gene underlying Dihc2, further detailed functional studies are clearly required to confirm its candidacy reverse-genetically by gene-modified animals. In conclusion, we suggest that SMEK2 is associated with diet-induced hypercholesterolemia in ExHC rats. Our finding provides new insight into the novel pathway underlying the responsiveness to dietary cholesterol in vivo.

Submitted on March 12, 2008
Revised on August 18, 2008


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
  1. Criqui, M. H. 1986. Epidemiology of atherosclerosis: an updated overview. Am. J. Cardiol. 57: 18C–23C.[CrossRef][Medline]

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  3. Dietschy, J. M., S. D. Turley, and D. K. Spady. 1993. Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans. J. Lipid Res. 34: 1637–1659.[Medline]

  4. McNamara, D. J., R. Kolb, T. S. Parker, H. Batwin, P. Samuel, C. D. Brown, and E. H. Ahrens, Jr. 1987. Heterogeneity of cholesterol homeostasis in man. Response to changes in dietary fat quality and cholesterol quality. J. Clin. Invest. 79: 1729–1739.[Medline]

  5. Ye, S. Q., and P. O. Kwiterovich, Jr. 2000. Influence of genetic polymorphisms on responsiveness to dietary fat and cholesterol. Am. J. Clin. Nutr. 72 (Suppl.): 1275–1284.

  6. Mashimo, T., H. Ogawa, Z. H. Cui, Y. Harada, K. Kawakami, J. Masuda, Y. Yamori, and T. Nabika. 2007. Comprehensive QTL analysis of serum cholesterol levels before and after a high-cholesterol diet in SHRSP. Physiol. Genomics. 30: 95–101.[Abstract/Free Full Text]

  7. Giesen, K., L. Plum, R. Kluge, J. Ortlepp, and H.-G. Joost. 2003. Diet-dependent obesity and hypercholesterolemia in the New Zealand obese mouse: identification of a quantitative trait locus for elevated serum cholesterol on the distal mouse chromosome 5. Biochem. Biophys. Res. Commun. 304: 812–817.[CrossRef][Medline]

  8. Lyons, MA. H. Wittenburg, R. Li, K. A. Walsh, G. A. Churchill, M. C. Carey, and B. Paigen. 2003. Quantitative trait loci that determine lipoprotein cholesterol levels in DBA/2J and CAST/Ei inbred mice. J. Lipid Res. 44: 953–967.[Abstract/Free Full Text]

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  10. Imaizumi, K., A. Nagatomi, M. Sato, A. Tominaga, and M. Sugano. 1992. Cholesterol metabolism in ExHC (exogenous hypercholesterolemic) rats. Biochim. Biophys. Acta. 1123: 101–109.[Medline]

  11. Asahina, M., M. Sato, and K. Imaizumi. 2005. Genetic analysis of diet-induced hypercholesterolemia in exogenously hypercholesterolemic rats. J. Lipid Res. 46: 2289–2294.[Abstract/Free Full Text]

  12. Markel, P., P. Shu, C. Ebeling, G. A. Carlson, D. L. Nagle, J. S. Smutko, and K. J. Moore. 1997. Theoretical and empirical issues for marker-assisted breeding of congenic mouse strains. Nat. Genet. 17: 280–284.[CrossRef][Medline]

  13. Sakono, M., H. Mori, K. Nagao, M. Sato, I. Ikeda, K. Yamamoto, and K. Imaizumi. 1996. Exogenous hypercholesterolemic rats, compared with their progenitor, Sprague-Dawley rats, promptly alter cholesterol metabolism in the liver and secrete cholesterol-rich particles in response to dietary cholesterol. Comp. Biochem. Physiol. B Biochem. Mol. Biol. 113: 803–808.[CrossRef][Medline]

  14. Lewis, G. F. 1997. Fatty acid regulation of very low density lipoprotein production. Curr. Opin. Lipidol. 8: 146–153.[Medline]

  15. Tsai, J., W. Qiu, R. Kohen-Avramoglu, and K. Adeli. 2007. MEK-ERK inhibition corrects the defect in VLDL assembly in HepG2 cells: potential role of ERK in VLDL-apoB100 particle assembly. Arterioscler. Thromb. Vasc. Biol. 27: 211–218.[Abstract/Free Full Text]

  16. Mendoza, M. C., F. Du, N. Iranfar, N. Tang, H. Ma, W. F. Loomis, and R. A. Firtel. 2005. Loss of SMEK, a novel conserved protein, suppresses mek1 null cell polarity, chemotaxis, and gene expression defects. Mol. Cell. Biol. 25: 7839–7853.[Abstract/Free Full Text]

  17. Baker, K. E., and R. Parker. 2004. Nonsense-mediated mRNA decay: terminating erroneous gene expression. Curr. Opin. Cell Biol. 16: 293–299.[CrossRef][Medline]


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