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Hypertriglyceridemia and Hepatic Steatosis in Senescence-Accelerated Mouse Associate to Changes in Lipid-Related Gene Expression

Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, School of Pharmacy, University of Barcelona and IBUB (Institute of Biomedicine University of Barcelona), Spain.

Address correspondence to Juan Carlos Laguna, PhD, Unitat de Farmacologia, Facultat de Farmacia, Avda Diagonal 643, Barcelona 08028, Spain. E-mail: jclagunae{at}ub.edu

Aged rodents show increasing plasma and tissue triglycerides, and reductions in liver peroxisome proliferator-activated receptor (PPAR) and its target genes. We determined whether a similar situation is present in a model of accelerated aging, the senescence-accelerated prone (SAM-P8) mouse. Five-month-old SAM-P8 mice were hypertriglyceridemic, and exhibited hepatic steatosis and reduced fatty acid oxidation versus control 5-month-old senescence-accelerated resistant (SAM-R1) mice, with no differences in PPAR expression and binding activity; in fact, fenofibrate administration to SAM-P8 mice induced a clear PPAR-driven response. Complementary DNA (cDNA) microarray analysis (Affymetrix Mouse Genome 430A 2.0 GeneChip array), Western blot, and electrophoretic mobility shift assay (EMSA) experiments indicated, among other changes, a deficit in farnesoid X receptor (FXR) expression and binding activity in the livers of SAM-P8 mice with respect to SAM-R1 controls. Triglyceride accretion and a deficit in hepatic fatty acid oxidation, features of the aging process in mammals, associate to a deficit in hepatic FXR activity in the SAM-P8 mice.

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