Ageing is a complex physiological process shaped by nutrition, metabolism and hormones, with insulin, responsible for glucose absorption from the blood, being an important pro-ageing factor. The metabolic decline observed in ageing is characterized by changes in insulin action and body fat distribution, predisposing to diseases (atherosclerosis, coronary vascular disease [CVD], hyperlipedemia, obesity, insulin resistance and type 2 diabetes mellitus [T2DM]).
Liver X receptors (LXRs) are nuclear receptors (NRs) that are important in regulating cholesterol, lipid and glucose metabolism. Despite the wealth of data supporting the role of LXRs in energy metabolism, the information is scarce regarding how they integrate multiple inputs in whole organisms across life span.
The present study was conducted both to investigate how LXRá affects the regulation of energy metabolism in a physiological setting and to study sexual dimorphism in ageing mice. As such, wild type (WT) and LXRá-/- C57BL/6 mice, both females and males, were included. They had free access to food and water throughout the experiment and were sacrificed at either 1, 3, 6 or 9 months of age. The relative mRNA expression levels of hepatic genes were revealed using qRT-PCR, and several components in serum were measured. Our data demonstrate that, in the presence or absence of LXRá, several hepatic genes are regulated in an age dependent and/or sex dependent fashion. From the results of this thesis, we suggest that several hepatic LXRá target genes are regulated during the ageing process, such as the de novo lipogenic genes (fatty acid synthase [FAS] and stearoyl-CoA dehydrogenase-1 [SCD-1]). Their mRNA expression levels at 1 month are dependent upon LXRá. A gradual increase in the expression of these genes, occur in LXRá-/- animals aged 1-9 months, indicating that other mechanisms/proteins come into play to compensate for the loss of LXRá. Furthermore, this is also the first report assessing the link between LXRá and circadian gene regulation. Our data show that LXRá is important in regulating the basal mRNA expression of the circadian gene, BMAL1, in 1 month old animals. It is therefore tempting to speculate that LXRá is involved in circadian signaling pathways. In addition, this study also reveals many differences between female and male mice, both in plasma glucose concentration, serum levels (i.e. insulin, triacylglycerol (TAG), cholesterol) and relative mRNA levels (i.e. ATP-binding cassette [ABC] cholesterol transporters ABCG5/G8, cholesterol 7 á-hydroxylase [CYP7A1], Fructose-1,6-bisphosphatase 1 [FBP-1], glucose transporter [GLUT] 2).
In order to further evaluate the potential role of LXRá in the ageing process through glucose and lipid metabolic control, the crosstalk with other tissues/organs, NRs, hormones and cofactors must be addressed, as no single pathway is believed to function in an isolated manner. Furthermore, it remains to be elucidated if similar differences are present in humans.