1. Hypertension. 2008 Jan;51(1):148-53. Epub 2007 Dec 10.
Identification of mutated Srebf1 as a QTL influencing risk for hepatic steatosis
in the spontaneously hypertensive rat.
Pravenec M(1), 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.
Author information:
(1)Institute of Physiology and Center for Applied Genomics, Academy of Sciences
of the Czech Republic, Prague, Czech Republic.
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.
PMID: 18071061 [PubMed - indexed for MEDLINE]
PUBMED: 18071061
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