[Show abstract][Hide abstract] ABSTRACT: Type 1 diabetes is characterized by T-cell-mediated autoimmune destruction of pancreatic β-cells. Currently, approximately 50 type 1 diabetes susceptibility genes or chromosomal regions have been identified. However, the functions of type 1 diabetes susceptibility genes in T cells are elusive. In this study, we evaluated the correlation between type 1 diabetes susceptibility genes and T-cell signaling. The expression levels of 22 candidate type 1 diabetes susceptibility genes in T cells from nonobese diabetic (NOD), control C57BL/6 (B6), and NOD-control F1 hybrid mice were analyzed in response to 2 key immunoregulatory cytokines: interleukin-2 (IL-2) and transforming growth factor β (TGF-β). Exogenous gene expression studies were also performed in EL4 and Jurkat E6.1 T-cell lines. Significant differences in the expression of Clec16a, Dlk1, Il2, Ptpn22, Rnls, and Zac1 (also known as Plagl1) were observed in T cells derived from the 3 strains of mice, and TGF-β differentially influenced the expression of Ctla4, Foxp3, Il2, Ptpn22, Sh2b3, and Zac1. We found that TGF-β induced Zac1 expression in both primary T cells and EL4 cells and that exogenous expression of Zac1 and ZAC1 in T -cell lines altered the expression of Il2 and DLK1, respectively. The results of our study indicate the possibility that additional genetic pathways underlying type 1 diabetes susceptibility, including those involving Clec16a, Dlk1, Rnls, Sh2b3, and Zac1 under IL-2 and TGF-β signaling in T cells, may be shared between human and NOD mice.
[Show abstract][Hide abstract] ABSTRACT: The quantitative trait locus (QTL) mapping in segregating crosses of NSY (Nagoya-Shibata-Yasuda) mice, an animal model of type 2 diabetes, with nondiabetic strain C3H/He mice has identified diabetogenic QTLs on multiple chromosomes. The QTL on chromosome 11 (Chr11) (Nidd1n) showing the largest effect on hyperglycemia was confirmed by our previous studies with homozygous consomic mice, C3H-11(NSY), in which the NSY-derived whole Chr11 was introgressed onto control C3H background genes. C3H-11(NSY) mice also showed a streptozotocin (STZ) sensitivity. In the present study, we constructed heterozygous C3H-11(NSY) mice and the phenotypes were analyzed in detail in comparison with those of homozygous C3H-11(NSY) and C3H mice. Heterozygous C3H-11(NSY) mice had significantly higher blood glucose levels and STZ sensitivity than those in C3H mice. Hyperglycemia and STZ sensitivity in heterozygous C3H-11(NSY) mice, however, were not as severe as in homozygous C3H-11(NSY) mice. The body weight and fat pad weight in heterozygous C3H-11(NSY) mice were similar to those in C3H and homozygous C3H-11(NSY) mice. These data indicated that the introgression of Chr11 of the diabetes-susceptible NSY strain onto diabetes-resistant C3H caused marked changes in the glucose tolerance and STZ susceptibility even in a heterozygous state, and suggested that the mode of inheritance of a gene or genes on Chr11 for hyperglycemia and STZ sensitivity is additive.
Journal of Diabetes Research 02/2013; 2013:608923. DOI:10.1155/2013/608923 · 2.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Both genetic factors and diabetogenic environmental factors, such as a high-sucrose diet (HSD), are involved in the development of type 2 diabetes. In this study, NSY mice, an animal model of type 2 diabetes and C3H mice used as controls, were fed a HSD, a high-fat diet (HFD) or a regular diet (RD) from weaning. In C3H mice, HFD significantly increased body weight gain, but maintained glucose tolerance. In contrast, in NSY mice, HSD resulted in increased body weight gain and liver steatosis and increased glucose intolerance to a greater extent than HFD. Furthermore, we performed DNA microarray analysis to detect differences in hepatic gene expression levels in both strains under HSD. We then performed RT-PCR analysis on selected genes to evaluate basal expression level under RD and changes under HSD conditions. HSD-fed NSY, but not C3H mice, exhibited increased hepatic expression levels of Pparg2, an isoform of Pparg as well as G0s2, a target of Pparg, which are known to be adipocyte-specific genes. Compared to RD-fed C3H mice, hepatic expression levels of Kat2b (transcriptional regulation), Hsd3b5 (steroid hormone metabolism) and Cyp7b1 (bile acid metabolism) were initially lower in RD-fed NSY mice, and were further decreased in HSD-fed NSY mice. Expression of Metallothionein (Mt1) and Metallothionein 2 (Mt2) was significantly lower in NSY mice compared to C3H mice, irrespective of dietary condition. These data suggest that elucidation of this heterogeneity in response to HSD might contribute to further understanding of the gene-environment interactions leading to diabetes in humans.
[Show abstract][Hide abstract] ABSTRACT: Diabetogenic loci for type 2 diabetes have been mapped to mouse chromosome (Chr) 11 and 14 in the Nagoya-Shibata-Yasuda (NSY) mouse, an animal model of type 2 diabetes. We aimed to obtain direct evidence of these genes on each chromosome and to clarify their function and interaction in conferring susceptibility to type 2 diabetes.
We established three consomic strains homozygous for diabetogenic NSY-Chr11, NSY-Chr14 or both on the control C3H background (C3H-11(NSY), C3H-14(NSY) and C3H-11(NSY)14(NSY), respectively), and monitored diabetes-related phenotypes longitudinally. The glucokinase gene was sequenced as a positional candidate gene on Chr11.
C3H-11(NSY) mice showed hyperglycaemia associated with impaired insulin secretion and age-dependent insulin resistance without obesity. C3H-14(NSY) mice exhibited hyperglycaemia mainly due to insulin resistance, with a slight increase in percentage body fat. C3H-11(NSY)14(NSY) double consomic mice showed marked hyperglycaemia and obesity, which was not observed in single consomic strains. Sequences of the glucokinase gene were allelically variant between NSY and C3H mice.
These data provide direct evidence that Chr11 and Chr14 harbour major susceptibility genes for type 2 diabetes. These two chromosomes interact to cause more severe hyperglycaemia and obesity, which was not observed with the presence of either single chromosome, indicating different modes of gene-gene interaction depending on the phenotype. Marked changes in the phenotypes retained in the consomic strains will facilitate fine mapping and the identification of the responsible genes and their interaction with each other, other genes and environmental factors.
[Show abstract][Hide abstract] ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is currently recognized as a global health issue and encompasses a wide spectrum of entities, ranging from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH). The lack of a spontaneous animal model of NASH, however, has hampered basic research in this field.
We examined the hepatic lesions in the inbred Fatty Liver Shionogi (FLS) mouse, which exhibits type 2 diabetes, and investigated the molecular mechanism leading to NAFLD/NASH. Using vector-mediated hepatic expression of microsomal triglyceride transfer protein (MTP), a key molecule for very low density lipoprotein (VLDL) assembly and export, its contribution to the hepatic lesions as well as to glucose intolerance was examined.
The FLS mouse, maintained on normal chow, exhibited excessive hepatic triglyceride (TG) accumulation due to impaired VLDL secretion, and subsequently hepatic lesions comparable to NASH, with increased expression of inflammatory molecules as well as insulin resistance. Gene expression and Western blot analyses demonstrated reduced hepatic expression of MTP in the FLS mouse. Hepatic induction of MTP resulted in a reduction in hepatic TG accumulation, improvement of VLDL export, and amelioration of NASH-like lesions, as well as glucose intolerance.
These data suggest that the FLS mouse could serve as a spontaneous model of NASH with insulin resistance, and that reduced MTP is involved in the development of NASH, pointing towards MTP as a critical target for the prevention and treatment of NASH.
Journal of Hepatology 03/2010; 52(6):903-12. DOI:10.1016/j.jhep.2009.12.033 · 11.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Given the potential for beta-cells to increase their mass, glucose intolerance might be ameliorated by a compensatory increase in beta-cell mass. However, it remains uncertain whether such amelioration is feasible in vivo. In this study, we investigated glucose tolerance, islet morphology, and islet gene expression of Fatty Liver Shionogi (FLS) mice, a model for non-alcoholic fatty liver disease (NAFLD). Relative to control mice, FLS mice showed an age-dependent increase in glucose intolerance up to the age of 24 weeks, leading to the development of diabetes. After this time, glucose tolerance ameliorated spontaneously and diabetes resolved by 48 week of age, associated with marked hyperinsulinemia. Islets of the FLS mice demonstrated a marked increase in beta-cell mass with an increase in beta-cell numbers. Islet gene expression analysis in FLS mice demonstrated no changes in gene expression of glucokinase or insulin receptor substrate 2. These data demonstrated that the 24-week-old FLS mouse is a model for type 2 diabetes with NAFLD and that the 48-week-old FLS mouse exhibits spontaneous amelioration of type 2 diabetes associated with augmented beta-cell number/mass.
[Show abstract][Hide abstract] ABSTRACT: A recent dramatic increase in elderly patients with diabetes mellitus has made the proper management of the disease in this population more important. Here, we discuss the present status of diabetes management in the elderly in Japan. As a characteristic feature of elderly persons, body weight reduction is difficult, because of the profound adaptive reduction in resting energy expenditure under calorie restriction in the elderly. However, hyperglycemia increases the risk for diabetic complications, except proliferative retinopathy, similarly in elderly and non-elderly. Of note, there is marked clinical heterogeneity in this generation in the following aspects: duration, complication status (past aspect), insulin secretion, insulin sensitivity, familial support and physical exercise/activity (present aspect), as well as the expected lifespan (future aspect). This heterogeneity among the elderly should render diabetes treatment diverse, and in fact, one of the largest surveys in Japan demonstrated significant diversity in diabetes management in the elderly. In Japan, thus, the present management of diabetes in the elderly is considerably diverse, reflecting the clinical heterogeneity among elderly patients with diabetes. Further clinical evidence is awaited for the establishment of proper and safe management of diabetes in the elderly.
Diabetes Research and Clinical Practice 10/2007; 77 Suppl 1(3):S82-6. DOI:10.1016/j.diabres.2007.01.038 · 2.54 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Obesity and fatty liver are commonly associated with type 2 diabetes, but the genetic and functional bases linking fatty liver with obesity and diabetes are largely unknown. Our aim was to investigate the association of fatty liver with obesity and other diabetes-related phenotypes and to define the genetic control of obesity and fatty liver.
We established 306 F2 mice by crossing Nagoya-Shibata-Yasuda (NSY) mice, an animal model of type 2 diabetes, with control C3H mice, and analysed their phenotypes. Whole-genome screening of F2 mice was performed to identify the loci responsible for fatty liver and obesity.
A strong association of fatty liver with obesity, hyperinsulinaemia and hyperglycaemia was observed in F2 mice. Using whole-genome screening in 306 F2 mice, we mapped a new locus for fatty liver (Fl1n) on chromosome 6 (maximum logarithm of odds score [MLS] 10.0) and one for body weight (Bw1n) on chromosome 7 (MLS 5.1). Fl1n was linked to epididymal fat weight as well as fatty liver, but its effects were opposite in the two tissues in that the NSY allele increased liver fat but decreased epididymal fat, suggesting a role of Fl1n in partitioning of fat mass. The sequence of peroxisome proliferator-activated receptor gamma (Pparg), a candidate for Fl1n, showed allelic variation between NSY and C3H mice.
These data suggest that fatty liver and obesity are phenotypically related but genetically independent. Loci homologous to Fl1n and Bw1n are good candidate genes for susceptibility to fatty liver and obesity in humans.
[Show abstract][Hide abstract] ABSTRACT: Multiple genes are involved in conferring susceptibility to autoimmune type 1 diabetes mellitus. The immunoreceptor programmed cell death-1 (PDCD-1), an inhibitory costimulatory molecule regulating peripheral tolerance, is reported to play an important role in the development of type 1 diabetes mellitus, making the human PDCD-1 gene, PDCD1, a candidate for disease susceptibility. The aim of this study was to clarify the contribution of PDCD1 to genetic susceptibility to type 1 diabetes mellitus in humans. To screen for sequence variants, we sequenced all 5 exons and exon-intron junctions of PDCD1 in Japanese subjects, 16 with type 1 diabetes mellitus and 16 without the disease. Some of the sequence variations identified were genotyped in larger samples (n = 275) with and without type 1 diabetes mellitus by polymerase chain reaction restriction fragment length polymorphism method or a fluorescence-based method. The distributions of polymorphisms were compared between patients with type 1 diabetes mellitus and healthy controls by contingency table analysis and Pearson chi(2) test. In this study, we found 16 sequence variants, including a TGC repeating variant in the 3' untranslated region. We found this variant to be associated with the development of type 1 diabetes mellitus. These data suggest the contribution of PDCD1 and its gene product to the development of type 1 diabetes mellitus.
[Show abstract][Hide abstract] ABSTRACT: A recent study in the nonobese diabetic (NOD) mouse demonstrated the involvement of interleukin (IL)-21 in the pathogenesis of type 1 diabetes. A strong susceptibility locus, Idd3, has also been mapped to the interval containing the murine gene for IL-21 (Il21), making Il21 and the human orthologue IL21 a functional and positional candidate gene for type 1 diabetes. To investigate the contribution of the human genes for IL-21 and its receptor (IL-21R) to susceptibility to type 1 diabetes, we re-sequenced IL21 to identify novel sequence variants, searched for informative variants of IL21R, and studied the association of these variants with the disease. Two polymorphisms, a single nucleotide polymorphism (SNP) and a mononucleotide repeat polymorphism, were identified for IL21, and an allele of the mononucleotide repeat polymorphism was positively associated with the disease. Two novel microsatellite polymorphisms of IL21R were identified, one of which was associated with the disease. Scoring of individuals according to the status of these alleles showed a significant trend for high scores for susceptibility in diabetes patients, suggesting the contribution of IL21 and IL21R to disease susceptibility in an additive manner. These data suggest a contribution of IL21 and IL21R to genetic susceptibility to type 1 diabetes and possible involvement of IL-21 and its receptor system in the disease pathogenesis.
Human Immunology 06/2007; 68(5):384-91. DOI:10.1016/j.humimm.2007.01.009 · 2.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bile acid-binding resins, such as cholestyramine and colestimide, have been clinically used as cholesterol-lowering agents. These agents bind bile acids in the intestine and reduce enterohepatic circulation of bile acids, leading to accelerated conversion of cholesterol to bile acids. A significant improvement in glycemic control was reported in patients with type 2 diabetes whose hyperlipidemia was treated with bile acid-binding resins. To confirm the effect of such drugs on glucose metabolism and to investigate the underlying mechanisms, an animal model of type 2 diabetes was given a high-fat diet with and without colestimide. Diet-induced obesity and fatty liver were markedly ameliorated by colestimide without decreasing the food intake. Hyperglycemia, insulin resistance, and insulin response to glucose, as well as dyslipidemia, were markedly and significantly ameliorated by the treatment. Gene expression of the liver indicated reduced expression of small heterodimer partner, a pleiotropic regulator of diverse metabolic pathways, as well as genes for both fatty acid synthesis and gluconeogenesis, by treatment with colestimide. This study provides a molecular basis for a link between bile acids and glucose metabolism and suggests the bile acid metabolism pathway as a novel therapeutic target for the treatment of obesity, insulin resistance, and type 2 diabetes.
[Show abstract][Hide abstract] ABSTRACT: A recombinant major histocompatibility complex (MHC) with the same class III region as the NOD mouse, but different class II region from the NOD mouse was identified in the NON mouse, and NOD mice congenic for this recombinant MHC, NOD.NON-H2, was established. None of the congenic mice homozygous for the NON MHC developed type 1 diabetes, indicating that the NOD MHC is necessary for the development of type 1 diabetes. A small portion of MHC heterozygotes developed late-onset type 1 diabetes, suggesting the contribution of class III MHC to type 1 diabetes susceptibility.
Annals of the New York Academy of Sciences 11/2006; 1079(1):114-7. DOI:10.1196/annals.1375.016 · 4.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although major histocompatibility complex (MHC)-linked susceptibility is the strongest component, recent studies demonstrated that MHC-linked susceptibility to type 1 diabetes consists of multiple components both in humans and non-obese diabetic (NOD) mouse. In the NOD mouse, Idd16 has been mapped to the region adjacent to, but distinct from Idd1 in the MHC class II region. Establishment of subcongenic NOD.CTS-H2 lines that possess the same MHC class II as the NOD mouse but non-NOD-derived chromosomal region in its adjacent regions, would facilitate further narrowing down of the localization of Idd16.
Annals of the New York Academy of Sciences 11/2006; 1079(1):118-21. DOI:10.1196/annals.1375.017 · 4.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The effect of hardness of the diet as an environmental factor on the development of diabetes was investigated in a mouse model of type 2 diabetes. NSY and control C3H/He mice were fed several types of dietary chow from 4 weeks of age. Autoclaved CRF-1, whose major components are almost the same as those of the MF diet except for increased pellet hardness, resulted in a significant reduction in body weight in both NSY (p<0.05) and C3H (p<0.001) mice at 16 weeks of age. The prevalence of diabetes in NSY mice fed autoclaved CRF-1 was significantly lower than that in those fed MF at 36 weeks of age (p<0.05), which was associated with a significant decrease in body weight (p<0.0001). At 16 weeks of age, NSY mice fed with a hard diet (autoclaved CRF-1) showed a significantly lower body weight (32.1+/-0.3g) and blood glucose levels during ipGTT than those with fed a normal (gamma-irradiated CRF-1) (35.6+/-1.3g, p<0.05 and <0.01, respectively) or soft (powdered CRF-1) (p<0.05 and <0.05, respectively) diet. Switching from normal (gamma-irradiated) to hard (autoclaved) chow, even after the development diabetes at 36 weeks of age, markedly improved glucose intolerance after 4 weeks in NSY mice despite the small change in body weight. These results indicate the importance of food hardness as an environmental factor in the development of type 2 diabetes.
Diabetes Research and Clinical Practice 10/2006; 74(1):1-7. DOI:10.1016/j.diabres.2006.03.031 · 2.54 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Among polygenes conferring susceptibility to type 1 diabetes in the NOD mouse, Idd10 on distal chromosome 3 has been shown to be important for disease susceptibility. In this study, we investigated the candidacy of Fcgr1 and Cd101 for Idd10, by congenic mapping and candidate gene sequencing. Among seven NOD-related strains studied, the IIS mouse was found to possess a recombinant Idd10 interval with the same sequence at Fcgr1 as the NOD mouse, but a different sequence at Cd101 from that in the NOD mouse with 10 amino acid substitutions. The frequency of type 1 diabetes in NOD mice congenic for IIS Idd10 (NOD.IISIdd10) was significantly reduced as compared to that in the NOD mouse, despite the presence of the identical Fcgr1 sequence. These data indicate that IIS mice possess a resistant allele at Idd10, and suggest that Cd101, but not Fcgr1, is responsible for the Idd10 effect.
Biochemical and Biophysical Research Communications 07/2005; 331(2):536-42. DOI:10.1016/j.bbrc.2005.04.005 · 2.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To increase our understanding of the effect of thiazolidinediones, a new class of antidiabetic drugs, on liver function as well as glycemic control, we investigated liver function before, during, and after treatment with troglitazone and pioglitazone. A total of 32 patients with type 2 diabetes were studied. Glycemic control and liver function were measured before, during, and after 4 to 12 weeks of treatment with troglitazone or pioglitazone. Glycemic control was assessed by fasting levels of plasma glucose, hemoglobin A 1c , and serum insulin, and liver function was assessed by asparatate aminotransferase (AST), alanine aminotransferase (ALT), and gamma -glutamyl transpeptidase ( gamma-GTP). Homeostasis model assessment for insulin resistance was used as an index of insulin resistance. During treatment with troglitazone, fasting plasma glucose and hemoglobin A 1c levels and homeostasis model assessment for insulin resistance were significantly decreased. Serum AST, ALT, and gamma-GTP levels were significantly decreased during treatment (AST, -17.4%; ALT, -27.2%; gamma-GTP, -47.9%) and returned to pretreatment levels after 4 weeks of withdrawal of the drug. A similar tendency was observed during treatment with pioglitazone (AST, -4.7%; ALT, -16.4%; gamma-GTP, -30.8%). These data suggest that, in contrast to the deterioration of liver function reported in a small subset of patients treated with troglitazone, treatment with thiazolidinediones was associated with a decrease in serum transaminases in most patients. The improvement in liver function parameters known to be associated with fatty liver in the present study, together with an improvement in fatty liver reported for another class of insulin sensitizers, biguanides, suggests that thiazolidinediones may have a beneficial effect on fatty liver.
[Show abstract][Hide abstract] ABSTRACT: To study the contribution of beta-cell vulnerability to susceptibility to diabetes, we studied beta-cell vulnerability to a single high dose of streptozotocin (STZ) in an animal model of type 2 diabetes, the NSY mouse, a sister strain of the STZ-sensitive NOD mouse, in comparison with the STZ-resistant C3H mouse. NSY mice were found to be extremely sensitive to STZ. Introgression of a single Chr 11, where STZ-sensitivity was mapped in the NOD mouse, from NSY mice converted STZ-resistant C3H mice to STZ-sensitive. Two nucleotide substitutions were identified in the nucleoredoxin gene, a positional and functional candidate gene for STZ-induced diabetes on Chr 11. These data, together with the co-localization of type 1 (Idd4) and type 2 (Nidd1n) susceptibility genes on Chr 11, suggest that the intrinsic vulnerability of pancreatic beta cells is determined by a gene or genes on Chr 11, which may also contribute to susceptibility to spontaneous diabetes.
Biochemical and Biophysical Research Communications 04/2005; 328(1):158-64. DOI:10.1016/j.bbrc.2004.12.149 · 2.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the intrafamilial clustering of type 1 and type 2 diabetes, an interview-based assessment of family history of diabetes was conducted. Outpatients with either type 1 (n = 23) or type 2 diabetes (n = 124), and non-diabetic subjects (n = 118) received an interview regarding the diabetic status of each of their family members. In patients with type 1 diabetes, 22% (5 out of 23) had a parental history of diabetes, and diabetes in these 5 parents was assessed as type 2 diabetes mellitus. The prevalence of parental diabetes in the type 1 diabetic probands (22%) was significantly higher (P < 0.05) than that in non-diabetic probands (7%, 8 out of 118). In probands with type 2 diabetes, the prevalence of parental diabetes was 39% (48 out of 124), which was significantly higher (P < 0.0005) than that in the non-diabetic probands (7%). In the type 2 diabetic probands, no significant difference was noted in the prevalence between paternal (19%, 23 out of 124) and maternal diabetes (23%, 28 out of 124), suggesting no preferential inheritance of maternal diabetes in this population. The present interview-based assessment of family history of diabetes suggested a common genetic basis between type 1 and type 2 diabetes.
Diabetes Research and Clinical Practice 12/2004; 66 Suppl 1:S91-5. DOI:10.1016/j.diabres.2003.09.018 · 2.54 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent studies have revealed that MHC-linked susceptibility to Type 1 diabetes is determined by multiple components. In the non-obese diabetic (NOD) mouse, a second component (Idd16) has been mapped to a region adjacent to, but distinct from Idd1 in the class II region. In this study, we investigated the class I K gene as a candidate gene for Idd16.
We determined the genomic sequences of the class I K gene as well as the reactivity of K molecules with monoclonal antibodies in the NOD mouse, the Cataract Shionogi (CTS) mouse, and the NOD.CTS-H-2 congenic strain, which possesses a resistance allele to Type 1 diabetes at the Idd16 on the NOD genetic background genes.
While the K sequence of the NOD mouse was identical to that of Kd type, ten nucleotide substitutions were identified in the CTS mouse compared with the NOD mouse. Of these, three were in exon 4, giving two amino acid substitutions, which were identical to those seen in KK type. These characteristics were retained in the NOD.CTS-H-2 congenic strain, which had a lower incidence and delayed onset of Type 1 diabetes owing to a resistance allele at Idd16. Lymphocytes from NOD.CTS-H2 congenic mice reacted with anti-Kd and anti-Kk monoclonal antibodies, reflecting the unique sequence of the K gene. The nucleotide sequence of the K gene in the non-obese non-diabetic (NON) mouse was also unique, consisting of a combination of Kk- and Kb-like sequences.
These data suggest that H2-K is unique in CTS and NON mice, and that allelic variation of the class I K gene may be responsible for Idd16.
[Show abstract][Hide abstract] ABSTRACT: The serum level of high-density lipoprotein cholesterol (HDL-c), which protects against the development of atherosclerosis, is under genetic control. However, the genetic components responsible for the serum HDL-c level are yet to be determined. A recent knockout mouse study demonstrated that hepatocyte nuclear factor-1 alpha (HNF-1 alpha) is an essential transcriptional regulator of HDL-c metabolism. In this study, the association of an HNF-1 alpha gene polymorphism, isoleucine (Ile) 27 leucine (Leu), with lipid parameters, in particular with serum HDL-c level, was studied in 356 unrelated Japanese men. Though no significant difference was observed in total cholesterol and triglyceride levels among the three genotypes, the serum HDL-c level was significantly associated with the genotype (P < 0.01, trend test). Subjects with the Ile/Ile genotype had low serum HDL-c levels, and those with the Leu/Leu genotype had high serum HDL-c levels. These results demonstrate that the HNF-1 alpha gene locus is associated with serum HDL-c level and suggest that the Ile27 allele is a risk marker for atherosclerosis.