Positional cloning of the combined hyperlipidemia gene Hyplip1

Bodnar, Jackie; Chatterjee, Arnab K.; Castellani, Lawrence W.; Ross, David A.; Ohmen, Jeffrey D.; Cavalcoli, James D.; Wu, Cunle; Dains, Katherine M.; Catanese, Joe; Chu, Michael A.; Sheth, Sonal S.; Charugundla, Kanti; Démant, Peter; West, David B.; Jong, Pieter J. de; Lusis, Aldons J.

doi:10.1038/ng811

Cited by 198 publications

(190 citation statements)

References 27 publications

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“…As a matter of fact, it has been reported that nuclear Trx are helpful for TNF-␣-induced activation of NF-B, a proinflammatory and procarcinogenic transcription factor Karin and Greten, 2005). In addition, the drug-resistance of cancer due to higher expression of thioredoxin (Sasada et al, 1996) and previously reported hyperlipidemic phenotype of the Txnip-deficient mice (Bodnar et al, 2002) are probably the two other examples of such detrimental effect of Trx system. In summary, this study suggests that besides its antioxidant function in maintenance of cellular redox homeostasis, Trx may act as a regulator for timely quenching excessive PPAR␣ signaling and controlling the expression levels of PPAR␣-regulated metabolic enzymes according to metabolic need.…”

Section: Discussionmentioning

confidence: 98%

Thioredoxin-mediated Negative Autoregulation of Peroxisome Proliferator-activated Receptor α Transcriptional Activity

Liu

Shen

2006

MBoC

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PPAR␣, a member of the nuclear receptor superfamily, and thioredoxin, a critical redox-regulator in cells, were found to form a negative feedback loop, which autoregulates transcriptional activity of PPAR␣. Thioredoxin was identified as a target gene of PPAR␣. Activation of PPAR␣ leads to increase of thioredoxin expression as well as its translocation from cytoplasm to nucleus, whereas ectopic overexpression of thioredoxin in the nucleus dramatically inhibited both constitutive and ligand-dependent PPAR␣ activation. As PPAR␣-target genes, the expression of muscle carnitine palmitoyltransferase I, medium chain acyl CoA dehydrogenase, and apolipoprotein A-I were significantly down-regulated by nucleus-targeted thioredoxin at transcriptional or protein level. The suppression of PPAR␣ transcriptional activity by Trx could be enhanced by overexpression of thioredoxin reductase or knockdown of thioredoxin-interacting protein, but abrogated by mutating the redox-active sites of thioredoxin. Mammalian one-hybrid assays showed that thioredoxin inhibited PPAR␣ activity by modulating its AF-1 transactivation domain. It was also demonstrated by electrophoretic mobility-shift assay that thioredoxin inhibited the binding of PPAR␣ to the PPAR-response element. Together, it is speculated that the reported negative-feedback loop may be essential for maintaining the homeostasis of PPAR␣ activity. INTRODUCTIONAs the first identified genetic sensor for fats, PPAR␣ is a ligandactivated transcription factor belonging to the nuclear receptor superfamily. The target genes of PPAR␣ are relatively homogenous group of genes that participate in various aspects of lipid catabolism such as fatty acid uptake through membranes, fatty acid binding in cells, fatty acid oxidation in microsomes, peroxisomes and mitochondria, and lipoprotein assembly and transportation (Lemberger et al., 1996). The significance of PPAR␣ in physiology and disease is evidenced by the fact that it and PPAR␥, another subtype of PPARs, are molecular targets for the lipid-lowering fibrate drugs and insulin-sensitizing thiazolidinedione (TZD), respectively (Evans et al., 2004). Besides activation of PPAR␣ by fatty acid and various exogenous ligands such as fibrates, the regulation of the PPAR␣ transcription activity by coactivators (Dowell et al., 1997), corepressors (Dowell et al., 1999), other transcription factors (TFs; Zhou et al., 1999), and posttranslational modifications including phosphorylation (Juge-Aubry et al., 1999) and ubiquination (Blanquart et al., 2002) have been extensively studied. However, redox regulation of PPAR␣ activity has not been reported so far.Multicellular organisms have evolved complex homeostatic mechanisms to sense and respond to a diverse range of exogenous and endogenous signals. It may be reasonable to expect some mechanisms that rapidly sense and tightly control the activity of PPAR␣ according to metabolic needs under normal physiological condition. Degradation of PPAR␣ by the ubiquitin-proteasome system and decrease of the ubiquitinat...

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Section: Discussionmentioning

confidence: 98%

Thioredoxin-mediated Negative Autoregulation of Peroxisome Proliferator-activated Receptor α Transcriptional Activity

Liu

Shen

2006

MBoC

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“…[3][4][5][6]. We excluded TXNIP, a causative gene for combined hyperlipidemia in mice 13 , and found that USF1 had significant association, linkage and shared haplotypes of the disease-associated alleles. The strongest evidence for association was Table 3 Haplotype analyses in men with elevated triglyceride levels using HBAT The inter-SNP distances and corresponding rs numbers for the SNPs f11r1s4-f11r1s6 and usf1s1-usf1s5 are shown in Table 2.…”

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confidence: 99%

“…Response to pest/pathogen/ parasite (13) Immune response (16) Response to external stimulus (17) Response to wounding (9) Upregulated genes Downregulated genes Figure 2 Distribution of genes according to functional category for the 16 upregulated and 60 downregulated genes for which annotation information for the Gene Ontology 26 class Biological process was available. In this analysis, lists of differentially expressed genes were examined for overrepresentation of functional classes, as defined by the Gene Ontology consortium, using the EASE tool 27 .…”

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confidence: 99%

Familial combined hyperlipidemia is associated with upstream transcription factor 1 (USF1)

et al. 2004

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Familial combined hyperlipidemia (FCHL), characterized by elevated levels of serum total cholesterol, triglycerides or both 1,2 , is observed in about 20% of individuals with premature coronary heart disease 1 . We previously identified a locus linked to FCHL on 1q21-q23 in Finnish families with the disease 3 . This region has also been linked to FCHL in families from other populations 4-6 as well as to type 2 diabetes mellitus 7-12 . These clinical entities have several overlapping phenotypic features, raising the possibility that the same gene may underlie the obtained linkage results. Here, we show that the human gene encoding thioredoxin interacting protein (TXNIP) on 1q, which underlies combined hyperlipidemia in mice 13 , is not associated with FCHL. We show that FCHL is linked and associated with the gene encoding upstream transcription factor 1 (USF1) in 60 extended families with FCHL, including 721 genotyped individuals (P = 0.00002), especially in males with high triglycerides (P = 0.0000009). Expression profiles in fat biopsy samples from individuals with FCHL seemed to differ depending on their carrier status for the associated USF1 haplotype. USF1 encodes a transcription factor known to regulate several genes of glucose and lipid metabolism 14-17 .To identify the gene on 1q21 associated with FCHL, we initially sequenced four functionally relevant regional candidates: TXNIP, USF1, retinoid X receptor gamma (RXRG) and apolipoprotein A-II (APOA2). In parallel, we carried out a functionally unbiased genetic analysis of 60 single-nucleotide polymorphisms (SNPs) in 26 genes in 42 families with FCHL, including the 31 families in the original linkage study 3 . We then genotyped the ten SNPs most likely to be relevant in the extended sample of 60 families of FCHL (Supplementary Table 1 online). Fifty SNPs were located in a 5.8-Mb region flanking the peak markers D1S104 and D1S1677 (Fig. 1). All the families that we studied included a proband with severe coronary heart disease and an abnormal lipid phenotype and an average of 5-6 members affected with FCHL.We sequenced the entire TXNIP gene and the 2,000-bp upstream DNA region in 60 FCHL probands. Of the 20 SNPs identified, none resulted in amino acid changes, and all were rare, with a maximal 7% allele frequency. We also did not observe the nonsense mutation causing hyperlipidemia in mice 13 . We genotyped the four most common SNPs in the 60 families with FCHL but found no evidence of association Table 2 for distances, SNP numbers and LD clusters of these SNPs). (c) The SNPs associated with triglyceride levels in men and (d) the SNPs associated with FCHL and triglycerides in all family members.

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“…21,22 In 1999, we identified a Trx-binding protein with a yeast two-hybrid assay and named it Trx-binding protein-2 (TBP-2); 23 it was recognized that TBP-2 is identical to vitamin D 3 upregulated protein-1 (VDUP-1) 24 or thioredoxin-interacting protein. 25 In a more recent work, we found that loss of TBP-2 plays an important role in human T-cell leukemia virus type I-induced T-cell transformation. 26 In the present study, we examined the significance of TBP-2 in the Fe-NTA-induced renal cancer model of rats.…”

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confidence: 99%

Two distinct mechanisms for loss of thioredoxin-binding protein-2 in oxidative stress-induced renal carcinogenesis

Dutta

Nishinaka

Masutani

et al. 2005

Laboratory Investigation

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Thioredoxin is a major component of thiol-reducing system. Recently, we identified thioredoxin-binding protein-2 (TBP-2) as a negative regulator of thioredoxin. Here, we report the role of TBP-2 in oxidative renal tubular injury and the subsequent carcinogenesis by ferric nitrilotriacetate. TBP-2 was abundantly expressed in the rat kidney. Immunohistochemical analysis revealed that TBP-2 was present in association with nuclei and mitochondrial intermembrane space in the proximal tubular cells and coimmunoprecipitated with cytochrome c. After acute oxidative tubular damage, TBP-2 protein, but not messenger RNA, markedly decreased, demonstrating shortened half-life of this protein. Most cases of the induced renal cell carcinoma showed undetectable levels of TBP-2 protein, which was associated with the methylation of CpG island in the promoter region. Genome sequence analyses identified the poly-A tract in the 3 0 untranslated region as a mutation hot spot in this rather nonselective environment. Collectively, the amounts of TBP-2 protein were inversely associated with proliferation of tubular cells, as evaluated by proliferating cell nuclear antigen. These results suggest that loss of TBP-2 is essential for proliferation of not only neoplastic but also non-neoplastic renal tubular cells, and that TBP-2 is a target gene in oxidative stress-induced renal carcinogenesis by ferric nitrilotriacetate.

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Positional cloning of the combined hyperlipidemia gene Hyplip1

Cited by 198 publications

References 27 publications

Thioredoxin-mediated Negative Autoregulation of Peroxisome Proliferator-activated Receptor α Transcriptional Activity

Thioredoxin-mediated Negative Autoregulation of Peroxisome Proliferator-activated Receptor α Transcriptional Activity

Familial combined hyperlipidemia is associated with upstream transcription factor 1 (USF1)

Two distinct mechanisms for loss of thioredoxin-binding protein-2 in oxidative stress-induced renal carcinogenesis

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