The spontaneously hypertensive rat (SHR) displays key features of the metabolic syndrome. To enable genetic dissection of complex traits, we developed HXB/BXH recombinant inbred (RI) strains derived from SHR and Brown Norway rats (N=30). We performed LC-MS–based metabolomic profiling of liver tissue, identifying 761 metabolites and more than 50 significant metabolomic QTLs (mQTLs; LOD >4) using GeneNetwork. A prominent mQTL on chromosome 11 regulating hepatic proline levels colocalized with a cis-eQTL for Prodh1, supporting its role in proline catabolism. An mQTL for N-alpha-acetylarginine on chromosome 4 overlapped a blood pressure QTL and a cis-eQTL for Nat8f1, suggesting a link between arginine acetylation and blood pressure regulation. Lipid-associated mQTLs near Cd36 colocalized with lipolysis QTLs, implicating Cd36 in hepatic lipid metabolism. Finally, mQTLs for microbial-derived metabolites on chromosome 3 overlapped a fat mass QTL, highlighting the gut–liver axis in adiposity regulation.

IPHYS contact person: Michal Pravenec, Laboratory of Genetics of Model Diseases; michal.pravenec@fgu.cas.cz