Separate and overlapping metabolic functions of LXRα and LXRβ in C57Bl/6 female mice

Korach-André, Marion; Parini, Paolo; Larsson, Lars-Olof; Arner, Anders; Steffensen, Knut R.; Gustafsson, Jan‐Åke

doi:10.1152/ajpendo.00184.2009

Cited by 49 publications

(57 citation statements)

References 40 publications

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“…3A). We have previously shown that LXRαβ −/− and LXRβ −/− mice but not LXRα −/− mice were protected against diet-induced obesity (18). In this respect, the mechanisms by which LXRα −/− mice showed similar fat content but higher UCP1 expression in both SC fat and BAT than WT mice on the ND remain unclear and have to be investigated further.…”

Section: Discussionmentioning

confidence: 96%

“…LXRαβ −/− and LXRβ −/− mice have been shown by our group and others to be resistant to high-fat diet-induced obesity (17,18,22). Several explanations have been proposed, such as increased EE or a resistance to insulin-induced lipid storage (17,18).…”

mentioning

confidence: 92%

“…BAT expresses high levels of peroxisome proliferator-activated receptor γ (PPARγ) (14) as well as liver-X receptors (LXRs) (15) and, consequently, is a target for nuclear receptor agonists. Although LXR function has been elucidated in detail with respect to cholesterol and lipid metabolism, recent findings have indicated that LXR is also an important modulator of glucose and water homeostasis as well as energy regulation (16)(17)(18)(19)(20)(21).…”

mentioning

confidence: 99%

“…Several explanations have been proposed, such as increased EE or a resistance to insulin-induced lipid storage (17,18). To our knowledge, however, the effect of deletion/activation of LXRs on glucose and lipid metabolism in brown adipocytes has not been explored in female C57BL/6 mice.…”

mentioning

confidence: 99%

“…Interestingly, GW3965 treatment together with the HCD significantly reduced food intake (FI) in WT mice compared with the HCD alone. LXRαβ −/− mice have been shown to be resistant to diet-induced obesity (17,18). Because resistance to diet-induced obesity can be the consequence of an increase of EE, oxygen consumption and carbon dioxide release were registered in WT and LXRαβ −/− mice after 3 wk on the HCD for 48 h in temperature-controlled (23°C) individual chambers.…”

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confidence: 99%

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Both liver-X receptor (LXR) isoforms control energy expenditure by regulating Brown Adipose Tissue activity

Korach-André

Archer

Barros

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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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.

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Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 92%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Both liver-X receptor (LXR) isoforms control energy expenditure by regulating Brown Adipose Tissue activity

Korach-André

Archer

Barros

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Nogo‐B receptor deficiency increases liver X receptor alpha nuclear translocation and hepatic lipogenesis through an adenosine monophosphate–activated protein kinase alpha–dependent pathway

Zhang

Chen

et al. 2016

Hepatology

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Nogo-B receptor (NgBR) was identified as a specific receptor for binding Nogo-B, and is essential for the stability of Niemann-Pick type C2 protein (NPC2) and NPC2-dependent cholesterol trafficking. Here, we report that NgBR expression levels decrease in the fatty liver and that NgBR plays previously unrecognized roles in regulating hepatic lipogenesis via NPC2-independent pathways. To further elucidate the pathophysiological role of NgBR in mammals, we generated NgBR liver-specific knockout mice and investigated the roles of NgBR in hepatic lipid homeostasis. Our results showed that NgBR knockout in mouse liver did not decrease either NPC2 levels or increase NPC2-dependent intracellular cholesterol levels. However, NgBR deficiency still resulted in remarkable cellular lipid accumulation that was associated with increased free fatty acids (FFA) and triglycerides (TG) in hepatocytes in vitro and in mouse livers in vivo. Mechanistically, NgBR deficiency specifically promotes the nuclear translocation of the liver X receptor alpha (LXRα) and increases the expression of LXRα-targeted lipogenic genes. LXRα knockout attenuates the accumulation of FFA and TG caused by NgBR deficiency. In addition, we elucidated the mechanisms by which NgBR bridges the AMP-activated protein kinase α (AMPKα) signaling pathway with LXRα nuclear translocation and LXRα-mediated lipogenesis. Our study demonstrates that NgBR is a specific negative regulator for LXRα–dependent hepatic lipogenesis and suggests that loss of NgBR is a potential trigger for inducing hepatic steatosis.

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Lipid‐sensing nuclear receptors in the pathophysiology and treatment of the metabolic syndrome

Vacca

Degirolamo

Mariani-Costantini

et al. 2011

WIREs Mechanisms of Disease

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Metabolic syndrome (MS) is a cluster of different diseases, namely central obesity, hypertension, hyperglycemia, and dyslipidemia, together with a pro-thrombotic and pro-inflammatory state. These metabolic abnormalities are often associated with an increased risk for cardiovascular disease (CVD) and cancer. Dietary and lifestyle modifications are currently believed more effective than pharmacological therapies in the management of MS patients. Nevertheless, the relatively low grade of compliance of patients to these recommendations, as well as the failure of current therapies, highlights the need for the discovery of new pharmacological and nutraceutic approaches. A deeper knowledge of the patho-physiological events that initiate and support the MS is mandatory. Lipid-sensing nuclear receptors (NRs) are the master transcriptional regulators of lipid and carbohydrate metabolism and inflammatory responses, thus standing as suitable targets. This review focuses on the physiological relevance of the NRs (peroxisome proliferator-activated receptors, liver X receptors, and farnesoid X receptor) in the control of whole-body homeostasis, with a special emphasis on lipid and glucose metabolism, and on the relationships between metabolic unbalances, systemic inflammation, and the onset of CVD. Future perspectives and possible clinical applications are also presented.

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Separate and overlapping metabolic functions of LXRα and LXRβ in C57Bl/6 female mice

Cited by 49 publications

References 40 publications

Both liver-X receptor (LXR) isoforms control energy expenditure by regulating Brown Adipose Tissue activity

Both liver-X receptor (LXR) isoforms control energy expenditure by regulating Brown Adipose Tissue activity

Nogo‐B receptor deficiency increases liver X receptor alpha nuclear translocation and hepatic lipogenesis through an adenosine monophosphate–activated protein kinase alpha–dependent pathway

Lipid‐sensing nuclear receptors in the pathophysiology and treatment of the metabolic syndrome

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