Hypertriglyceridemia and hepatic steatosis in senescence-accelerated mouse associate to changes in lipid-related gene expression.
Aged rodents show increasing plasma and tissue triglycerides, and reductions in liver peroxisome proliferator-activated receptor alpha (PPARalpha) 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 PPARalpha expression and binding activity; in fact, fenofibrate administration to SAM-P8 mice induced a clear PPARalpha-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.
Vilà
Laia
L
Department of Pharmacology and Therapeutic Chemistry, University of Barcelona, Barcelona, Spain.
Roglans
Núria
N
Alegret
Marta
M
Camins
Antoni
A
Pallàs
Mercè
M
Sánchez
Rosa María
RM
Vázquez-Carrera
Manuel
M
Laguna
Juan Carlos
JC
D000375:Aging / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism*; D011345:Fenofibrate / Q000008:administration & dosage / Q000494:pharmacology; D005786:Gene Expression Regulation; D015228:Hypertriglyceridemia / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D051379:Mice; D023421:Models, Animal; D010641:Phenotype; D012313:RNA / Q000032:analysis; D011897:Random Allocation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric
D012313:RNA; D011345:Fenofibrate