RGD Reference Report - Identification of mutated Srebf1 as a QTL influencing risk for hepatic steatosis in the spontaneously hypertensive rat. - Rat Genome Database

Send us a Message



Submit Data |  Help |  Video Tutorials |  News |  Publications |  Download |  REST API |  Citing RGD |  Contact   

Identification of mutated Srebf1 as a QTL influencing risk for hepatic steatosis in the spontaneously hypertensive rat.

Authors: Pravenec, M  Kazdova, L  Landa, V  Zidek, V  Mlejnek, P  Simakova, M  Jansa, P  Forejt, J  Kren, V  Krenova, D  Qi, N  Wang, JM  Chan, D  Aitman, TJ  Kurtz, TW 
Citation: Pravenec M, etal., Hypertension. 2008 Jan;51(1):148-53. Epub 2007 Dec 10.
RGD ID: 1643359
Pubmed: PMID:18071061   (View Abstract at PubMed)
DOI: DOI:10.1161/HYPERTENSIONAHA.107.100743   (Journal Full-text)

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) are consistent with the results of association studies indicating that common polymorphisms affecting SREBP-1 may influence cholesterol synthesis in humans and (2) indicate that variation in Srebf1 may influence risk for hepatic steatosis.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Hpcl2Ratsteatotic liver disease susceptibilityIAGP  RGD 
SHR.BN-(D10Mgh3-Srebf1)/IpcvRatsteatotic liver disease susceptibilityIAGP  RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Srebf1Ratcholesterol metabolic process  IMP  RGD 
Srebf1_v2Ratcholesterol metabolic process  IMP  RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Srebf1Ratdecreased cholesterol level  IAGP  RGD 
Srebf1_v2Ratdecreased cholesterol level  IAGP  RGD 
SHR.BN-(D10Mgh3-D10Rat85)/IpcvRatdecreased liver cholesterol level inducedIMPcontrolled cholesterol content dietcompared to SHR.BN-D10Mgh3-Srebf1/IpcvRGD 
SHR.BN-(D10Mgh3-D10Rat85)/IpcvRatdecreased liver triglyceride level inducedIMPcontrolled cholesterol content dietcompared to SHR.BN-D10Mgh3-Srebf1/IpcvRGD 
Hpcl2Ratincreased cholesterol level susceptibilityIDA  RGD 
SHR-Tg(PEPCK-SREBF1)1IpcvRatincreased liver cholesterol level inducedIMPcontrolled cholesterol content dietcompared to SHR/OlaIpcvRGD 
SHR.BN-(D10Mgh3-Srebf1)/IpcvRatincreased liver cholesterol level inducedIMPcontrolled cholesterol content dietcompared to SHR/OlaIpcv and SHR.BN-D10Mgh3-D10Rat85/IpcvRGD 

Related Phenotype Data for this Reference

Phenominer Options:  View all phenotype data for this reference  |  Download all phenotype data for this reference

Select a value below to view phenotype data for a specific strain, measurment, or condition.

Objects Annotated

Genes (Rattus norvegicus)
Srebf1  (sterol regulatory element binding transcription factor 1)
Srebf1_v2  (sterol regulatory element binding factor 1, variant 2)

QTLs
Hpcl2  (Hepatic cholesterol level QTL 2)


Additional Information