Identification of a mutation in ADD1/SREBP-1 in the spontaneously hypertensive rat

Pravenec, Michal; Jansa, P; Kostka, Vlastimil; Zidek, Vaclav; Křen, Vladimı́r; Forejt, Jiřı́; Kurtz, Theodore W.

doi:10.1007/s003350010273

Cited by 16 publications

(11 citation statements)

References 15 publications

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“…The relative activities of the two SREBP-1 isoforms differ: SREBP-1a is a potent activator of all SREBP-responsive genes, owing to its long transactivation domain encoded by its first exon, while in SREBP-1c, this exon encodes a shorter transactivation domain that is less potent than SREBP-1a (Horton et al 2002). SH rats carry a valine to methionine substitution in the COOH terminal regulatory domain of SREBP-1; since SREBP-1a and SREBP-1c are derived from a different splicing of the same gene, with a nearly identical COOH terminal domain, the substitution is expected to be present in both isoforms (Pravenec et al 2001).…”

Section: Aamentioning

confidence: 99%

Influence of genotype on the modulation of gene and protein expression by n-3 LC-PUFA in rats

et al. 2013

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It is becoming increasingly apparent that responsiveness to dietary fat composition is heterogeneous and dependent on the genetic make-up of the individual. The aim of this study was to evidence a genotype-related differential effect of n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA) on the modulation of hepatic genes involved in cholesterol metabolism. Fourteen spontaneously hypertensive (SH) rats, which present a naturally occurring variation in the gene encoding for sterol responsive element binding protein 1 (SREBP-1), contributing to their inherited variation in lipid metabolism, and 14 Wistar-Kyoto (WK) rats were fed a control diet or an n-3 LC-PUFA enriched diet for 90 days. Plasma lipid profile, total lipid fatty acid composition in plasma and liver, and the expression of SREBP-1 and 2, 3-hydroxy-3-methyl-glutaryl-CoA reductase, low-density lipoprotein receptor, and acyl-CoA:cholesterol acyltransferase 2 encoding genes and proteins were determined. The positive effect of the enriched diet on the serum lipid profile, particularly on total cholesterol and triglyceride level, was clearly evidenced in both WK and SH rats, but n-3 LC-PUFA acted through a different modulation of gene and protein expression that appeared related to the genetic background. Our study evidences a different transcriptional effect of specific nutrients related to genetic variants.

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Section: Aamentioning

confidence: 99%

Influence of genotype on the modulation of gene and protein expression by n-3 LC-PUFA in rats

et al. 2013

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“…Only recently Hajri et al (8) assessed the extent of functional defect in CD36/FAT, concluding that SHR indeed exhibits loss of CD36 function in fatty acid uptake in the adipose, heart, and oxidative muscle tissues. The SHR was shown to bear additional genetic variations contributing to the IRS phenotype (19), and some of them, like a mutation in sterol regulatory element binding protein-1c (SREBP-1c) (18), are directly involved in the regulation of fatty acid metabolism. Therefore, we used a congenic strain, carrying only 10-cM region of SHR origin with the defective Cd36/Fat allele.…”

Section: Effect Of Rsg On Metabolic Profile Of Bn/cub and Bnshr4mentioning

confidence: 99%

Rosiglitazone fails to improve hypertriglyceridemia and glucose tolerance in CD36-deficient BN.SHR4 congenic rat strain

Šeda

Kazdová²,

Křenová

et al. 2003

Physiological Genomics

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The favorable metabolic effects of thiazolidinediones are supposedly related to the peroxisome proliferator-activated receptor-γ (PPARγ)-driven changes in lipid metabolism, particularly in free fatty acid (FFA) trafficking. The fatty acid translocase CD36 is one of the proposed PPARγ targets to mediate this action. We assessed the effect of rosiglitazone (RSG, Avandia) administration in two inbred rat strains, BN/Cub and BN.SHR4 congenic strain, differing in 10 cM proximal segment of chromosome 4. Rats were fed high-sucrose diet with or without RSG for 1 wk. In BN.SHR4, which carries defective Cd36 allele of SHR origin, RSG failed to improve glucose tolerance (assessed by the oral glucose tolerance test), did not lower triglyceridemia, nor induced increases in epididymal and retroperitoneal adipose tissue weights and adipose tissue glucose utilization, effects observed in BN/Cub. On the other hand, the RSG-treated BN.SHR4 showed lower concentrations of FFA and substantial increase in glycogen synthesis and glucose oxidation in skeletal muscle. Altogether, these results support involvement of CD36 in RSG action, suggesting this pharmacogenetic interaction may be of particular importance in CD36-deficient humans.

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“…6 However, in transfection studies with SHR and BN cDNAs and a sterol regulatory element-1 reporter plasmid, we have been unable to detect any functional effect of this coding sequence variant on SREBP-1 activity (T.K. and M.P., unpublished observations, 2002).…”

Section: Sequence Analysis and Transfection Studiesmentioning

confidence: 99%

“…We used a simple sequence length polymorphism (SSLP) to distinguish the SHR and BN alleles for D10Mgh3 10 and a restriction fragment length polymorphism (RFLP) to distinguish the strain alleles for Srebf1. 6 We substituted the BN allele for Srebf1 on the SHR genetic background because the SHR background has proven favorable for identifying effects of other DNA variants on lipid metabolism. [11][12][13] We then compared hepatic cholesterol levels in the SHR congenic strain and SHR progenitor strain fed a high-cholesterol diet as described further below.…”

Section: Shr Congenic Strain and Subline Derivationmentioning

confidence: 99%

“…5 We subsequently found that the SHR harbors a rare allele of the gene encoding sterol regulatory element binding protein 1 (SREBP-1) that maps to a region of rat Chromosome 10 overlapping the QTL regulating hepatic cholesterol levels. 6 The gene for SREBP-1 (Srebf1) has 2 alternate promoters and codes for 2 protein isoforms designated SREBP-1a and SREBP-1c, both of which are well known transcriptional regulators of hepatic cholesterol and fatty acid synthesis. 7 SREBP-2 is another SREBP isoform that is considered to play a greater role in the regulation of cholesterol biosynthesis than the SREBP-1 isoforms.…”

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Identification of Mutated Srebf1 as a QTL Influencing Risk for Hepatic Steatosis in the Spontaneously Hypertensive Rat

Zidek¹,

Mlejnek²,

Šimáková³

et al. 2008

Atherosclerosis Supplements

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Abstract-Approximately 30% of patients with hypertension have hepatic steatosis, and it has recently been proposed that fatty liver be considered a feature of the metabolic syndrome. Obesity, diet, and level of physical activity are likely factors modulating risk for hepatic steatosis, however genetic factors could also influence susceptibility or resistance to fatty liver in hypertensive or normotensive subjects. In genetic studies in spontaneously hypertensive rats (SHRs) and Brown Norway (BN) rats, we discovered that a variant form of sterol regulatory element binding transcription factor 1 (Srebf1 gene, SREBP-1 protein) underlies a quantitative trait locus (QTL) influencing hepatic cholesterol levels in response to a high cholesterol diet. Compared with the BN allele of Srebf1, the SHR allele of Srebf1 includes variants in the promoter and coding regions that are linked to hepatic deficiency of SREBP-1 mRNA and protein, reduced expression of the SREBP-1 target gene stearoyl-CoA desaturase 1, reduced promoter activity for SREBP-1c, and relative protection from dietary induced accumulation of liver cholesterol. Genetic correction of reduced SREBP-1 activity by derivation of congenic and transgenic strains of SHR increased hepatic cholesterol levels, thereby confirming Srebf1 as a QTL influencing hepatic lipid metabolism in the rat. The Srebf1 variant regulating hepatic cholesterol did not appear to affect blood pressure. These findings (1) Key Words: fatty liver Ⅲ quantitative trait loci Ⅲ rats Ⅲ inbred SHR Ⅲ metabolic syndrome X Ⅲ hypertension Ⅲ sterol regulatory element binding protein 1

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Identification of a mutation in ADD1/SREBP-1 in the spontaneously hypertensive rat

Cited by 16 publications

References 15 publications

Influence of genotype on the modulation of gene and protein expression by n-3 LC-PUFA in rats

Influence of genotype on the modulation of gene and protein expression by n-3 LC-PUFA in rats

Rosiglitazone fails to improve hypertriglyceridemia and glucose tolerance in CD36-deficient BN.SHR4 congenic rat strain

Identification of Mutated Srebf1 as a QTL Influencing Risk for Hepatic Steatosis in the Spontaneously Hypertensive Rat

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