👤 Marion Korach-André

The liver X receptors (LXR)α and LXRβ are transcription factors belonging to the nuclear receptor family, which play a central role in metabolic homeostasis, being master regulators of key target genes in the glucose and lipid pathways. Wild-type (WT), LXRα(-/-), and LXRβ(-/-) mice were fed a chow diet with (treated) or without (control) the synthetic dual LXR agonist GW3965 for 5 wk. GW3965 raised intrahepatic triglyceride (TG) level but, surprisingly, reduced serum TG level through the activation of serum lipase activity. The serum TG reduction was associated with a repression of both catecholamine-stimulated lipolysis and relative glucose incorporation into lipid in isolated adipocytes through activation of LXRβ. We also demonstrated that LXRα is required for basal (nonstimulated) adipocyte metabolism, whereas LXRβ acts as a repressor of lipolysis. On the contrary, in skeletal muscle (SM), the lipogenic and cholesterol transporter LXR target genes were markedly induced in WT and LXRα(-/-) mice and to a lesser extent in LXRβ(-/-) mice following treatment with GW3965. Moreover, TG content was reduced in SM of LXRβ(-/-) mice, associated with increased expression of the main TG-lipase genes Hsl and Atgl. Energy expenditure was increased, and a switch from glucose to lipid oxidation was observed. In conclusion, we provide evidence that LXR might be an essential regulator of the lipid balance between tissues to ensure appropriate control of the flux of fuel. Importantly, we show that, after chronic treatment with GW3965, SM becomes the target tissue for LXR activation, as opposed to liver, in acute treatment. Show less

The liver plays a pivotal role in the physiological adaptation to fasting and a better understanding of the metabolic adaptive responses may give hints on new therapeutic strategies to control the metabolic diseases. The liver X receptors (LXRs) are well-established regulators of lipid and glucose metabolism. More recently fibroblast growth factor 21 (FGF21) has emerged as an important regulator of energy homeostasis. We hypothesized that the LXR transcription factors could influence Fgf21 expression, which is induced in response to fasting. Wild-type, LXRα(-/-), and LXRβ(-/-) mice were treated for 3 d with vehicle or the LXR agonist GW3965 and fasted for 12 h prior to the killing of the animals. Interestingly, serum FGF21 levels were induced after fasting, but this increase was blunted when the mice were treated with GW3965 independently of genotypes. Compared with wild-type mice, GW3965-treated LXRα(-/-) and LXRβ(-/-) mice showed improved insulin sensitivity and enhanced ketogenic response at fasting. Of note is that during fasting, GW3965 treatment tended to reduce liver triglycerides as opposed to the effect of the agonist in the fed state. The LXR-dependent repression of Fgf21 seems to be mainly mediated by the recruitment of LXRβ onto the Fgf21 promoter upon GW3965 treatment. This repression by LXRβ occurs through the recruitment and stabilization of the repressor complex composed of retinoid-related orphan receptor-α/Rev-Erbα/histone deacetylase 3 onto the Fgf21 promoter. Our data clearly demonstrate that there is a cross talk between the LXR and FGF21 signaling pathways in the adaptive response to fasting. Show less

Liver X receptor (LXR)α regulates the genes involved in cholesterol, fatty acid and glucose metabolism. Soy protein (SP) consumption reduces the hepatic accumulation of cholesterol and triacylglycerol, and improves insulin sensitivity. However, it is not known whether these effects are mediated via LXRα. We therefore investigated whether the consumption of SP regulates metabolic changes in cholesterol metabolism and insulin sensitivity via LXRα. Wild-type (WT) and Lxrα(-/-) (Lxrα, also known as Nr1h3) mice were fed an SP diet with or without cholesterol for 28 days. The expression of LXRα target genes was measured in liver and intestine, as were hepatic lipid content and faecal bile acid concentration. Oral glucose and insulin tolerance tests were also performed. Hepatocytes were used to study the effect of isoflavones on LXR activity. The livers of WT and Lxrα(-/-) mice fed an SP high-cholesterol diet showed less steatosis than those fed casein. The SP diet increased the expression of the ATP-binding cassette (ABC) sub-family genes Abca1, Abcg5 and Abcg8 in the liver and intestine, as well as increasing total faecal bile acid excretion and insulin sensitivity in WT mice compared with mice fed a casein diet. However, these effects of SP were not observed in Lxrα(-/-) mice. The SP isoflavone, genistein, repressed the activation of LXRα target genes by T0901317, whereas it stimulated the activation of LXRβ target genes. The AMP-activated protein kinase inhibitor, compound C, had the opposite effects to those of genistein. Our results suggest that SP isoflavones stimulate the phosphorylation of LXRα or LXRβ, resulting in different biological effects for each LXR isoform. Show less

Brown adipocytes are multilocular lipid storage cells that play a crucial role in nonshivering thermogenesis. Uncoupling protein 1 (UCP1) is a unique feature of brown fat cells that allows heat generation on sympathetic nervous system stimulation. As conventional transcriptional factors that are activated in various signaling pathways, liver-X receptors (LXRs) play important roles in many physiological processes. The role of LXRs in the regulation of energy homeostasis remains unclear, however. Female WT, LXRαβ(-/-), LXRα(-/-), and LXRβ(-/-) mice were fed with either a normal diet (ND) or a high-carbohydrate diet (HCD) supplemented with or without GW3965-LXR agonist. LXRαβ(-/-) mice exhibited higher energy expenditure (EE) as well as higher UCP1 expression in brown adipose tissue (BAT) compared with WT mice on the HCD. In addition, long-term treatment of WT mice with GW3965 showed lower EE at thermoneutrality (30 °C) and lower Ucp1 expression level in BAT. Furthermore, H&E staining of the BAT of LXRαβ(-/-) mice exhibited decreased lipid droplet size compared with WT mice on the HCD associated with a more intense UCP1-positive reaction. Quantification of triglyceride (TG) content in BAT showed lower TG accumulation in LXRβ(-/-) mice compared with WT mice. Surprisingly, GW3965 treatment increased TG content (twofold) in the BAT of WT and LXRα(-/-) mice but not in LXRβ(-/-) mice. Furthermore, glucose transporter (GLUT4) in the BAT of LXRα(-/-) and LXRβ(-/-) mice was sixfold and fourfold increased, respectively, compared with WT mice on the ND. These findings suggest that LXRα as well as LXRβ could play a crucial role in the regulation of energy homeostasis in female mice and may be a potential target for the treatment of obesity and energy regulation. Show less

The two liver X receptors (LXRs), LXRalpha and LXRbeta, are transcriptional regulators of cholesterol, lipid, and glucose metabolism and are both activated by oxysterols. Impaired metabolism is linked with obesity, insulin resistance, and type 2-diabetes (T2D). In the present study, we aimed to delineate the specific roles of LXRalpha and -beta in metabolic processes. C57Bl/6 female mice were fed a normal or a high-fat diet (HFD) and metabolic responses in wild-type, LXRalpha(-/-), LXRbeta(-/-), and LXRalphabeta(-/-) mice were analyzed. Whole body fat and intramyocellular lipid contents were measured by nuclear magnetic resonance. Energy expenditure was measured in individual metabolic cages. Glucose, insulin, and pyruvate tolerance tests were performed and gene expression profiles analyzed by qPCR. We found that both LXRbeta(-/-) and LXRalphabeta(-/-) mice are resistant to HFD-induced obesity independently of the presence of high cholesterol. Using tolerance tests, we found that, on an HFD, LXRbeta(-/-) mice enhanced their endogenous glucose production and became highly insulin resistant, whereas LXRalpha(-/-) and LXRalphabeta(-/-) mice remained glucose tolerant and insulin sensitive. Gene expression profiling confirmed that LXRbeta is the regulator of lipogenic genes in visceral white adipose tissue (WAT) and muscle tissue and, surprisingly, that Ucp1 and Dio2 are not responsible for the protection against diet-induced obesity observed in LXRbeta(-/-) and LXRalphabeta(-/-) mice. LXRalpha is required for the control of cholesterol metabolism in the liver, while LXRbeta appears to be a major regulator of glucose homeostasis and energy utilization and of fat storage in muscle and WAT. We conclude that selective LXRbeta agonists would be novel pharmaceuticals in the treatment of T2D. Show less