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(Hypertension. 2008;51:148.)
© 2008 American Heart Association, Inc.

Original Articles

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

Michal Pravenec; Ludmila Kazdova; Vladimir Landa; Vaclav Zidek; Petr Mlejnek; Miroslava Simakova; Petr Jansa; Jiri Forejt; Vladimir Kren; Drahomira Krenova; Nathan Qi; Jia-Ming Wang; Derrick Chan; Timothy J. Aitman; Theodore W. Kurtz

From the Institute of Physiology and Center for Applied Genomics (M.P., V.L., V.Z., P.M., M.S., V.K.), Academy of Sciences of the Czech Republic, Prague, Czech Republic; the Institute for Clinical and Experimental Medicine (L.K.), Prague, Czech Republic; the Institute of Molecular Genetics and Center for Applied Genomics (P.J., J.F.), Czech Academy of Sciences, Prague, Czech Republic; the Institute of Biology and Medical Genetics (M.P., V.K., D.K.), First Medical Faculty, Charles University, Prague, Czech Republic; the University of Michigan Medical School (N.Q.), Ann Arbor; the Department of Laboratory Medicine (J.-M.W., D.C., T.W.K.), University of California, San Francisco; and the MRC Clinical Sciences Centre (T.J.A.), Faculty of Medicine, Imperial College, London, UK.

Correspondence to Theodore Kurtz, MD, UCSF Department of Laboratory Medicine, 185 Berry Street, Suite 290, San Francisco, CA 94107. E-mail KurtzT{at}Labmed2.ucsf.edu

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.

Key Words: fatty liver • quantitative trait loci • rats • inbred SHR • metabolic syndrome X • hypertension • sterol regulatory element binding protein 1