Identification of mutated Srebf1 as a QTL influencing risk for hepatic steatosis in the spontaneously hypertensive rat.
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.
Pravenec
Michal
M
Institute of Physiology and Center for Applied Genomics, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Kazdova
Ludmila
L
Landa
Vladimir
V
Zidek
Vaclav
V
Mlejnek
Petr
P
Simakova
Miroslava
M
Jansa
Petr
P
Forejt
Jiri
J
Kren
Vladimir
V
Krenova
Drahomira
D
Qi
Nathan
N
Wang
Jia-Ming
JM
Chan
Derrick
D
Aitman
Timothy J
TJ
Kurtz
Theodore W
TW
D000483:Alleles; D000818:Animals; D030801:Animals, Genetically Modified; D001794:Blood Pressure / Q000502:physiology; D002784:Cholesterol / Q000378:metabolism; D005234:Fatty Liver / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006973:Hypertension / Q000150:complications / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D008297:Male; D009154:Mutation / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics*; D051381:Rats; D011914:Rats, Inbred BN; D011918:Rats, Inbred SHR; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics* / Q000378:metabolism
C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D002784:Cholesterol