Altered cholesterologenic and lipogenic transcriptional profile in livers of aging Snell dwarf (Pit1dw/dwJ) mice

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Abstract
Summary: Several murine models demonstrate that mammalian longevity can be increased by single gene mutations affecting endocrine signalling, particularly via the GH/IGF‐1 axis. In this study, we identify age‐independent patterns of hepatic gene expression characteristic of long‐lived Snell (Pit1dw/dwJ) dwarf mice. Comparative microarray analysis of young and aged male livers was performed to discover specific genes differentially expressed between Pit1dw/dwJ and control mice. Further examination by real‐time RT‐PCR confirmed that transcripts encoding HMG‐CoA synthase‐1, HMG‐CoA reductase, farnesyl diphosphate synthase, isopentenyl pyrophosphate isomerase, mevalonate decarboxylase, squalene epoxidase, lanosterol demethylase, malic enzyme and apolipoprotein A‐IV were significantly decreased in both male and female Pit1dw/dwJ livers at 3–5 and 24–28 months of age. In contrast, transcripts encoding the β3‐adrenergic receptor, lipoprotein lipase, PPARγ and a very low‐density lipoprotein receptor homologue were increased significantly in dwarf livers relative to age‐matched controls. These studies reveal enduring transcriptional changes characteristic of Pit1dw/dwJ dwarf mice that involve genes regulating cholesterol biosynthesis, fatty acid metabolism and lipoprotein homeostasis. Linked to global energy metabolism, this stable shift in hepatic gene expression may contribute to longevity determination by influencing particular metabolic functions often compartmentalized within the mitochondrion and peroxisome; further this metabolic shift may also parallel many transcriptional changes induced by caloric restriction.