Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR

Nuclear receptors are integrators of hormonal and nutritional signals, mediating changes to metabolic pathways within the body. Given that modulation of lipid and glucose metabolism has been linked to diseases including type 2 diabetes, obesity and atherosclerosis, a greater understanding of pathways that regulate metabolism in physiology and disease is crucial. The liver X receptors (LXRs) and the farnesoid X receptors (FXRs) are activated by oxysterols and bile acids, respectively. Mounting evidence indicates that these nuclear receptors have essential roles, not only in the regulation of cholesterol and bile acid metabolism but also in the integration of sterol, fatty acid and glucose metabolism.     

LXRbeta is required for adipocyte growth, glucose homeostasis, and beta cell function

Liver X receptors (LXR) alpha and beta are nuclear oxysterol receptors with established roles in cholesterol, lipid, and carbohydrate metabolism. Although LXRs have been extensively studied in liver and macrophages, the importance for development and metabolism of other tissues and cell types is not as well characterized. We demonstrate here that although LXRalpha and LXRbeta are not required for adipocyte development per se, LXRbeta is required for the increase in adipocyte size that normally occurs with aging and diet-induced obesity. Similar food intake and oxygen consumption in LXRbeta-/- mice suggests that reduced storage of lipid in adipose tissue is not due to altered energy balance. Despite reduced amounts of adipose tissue, LXRbeta-/- mice on a chow diet have insulin sensitivity and levels of adipocyte hormones similar to wild type mice. However, these mice are glucose-intolerant due to impaired glucose-induced insulin secretion. Lipid droplets in pancreatic islets may result from accumulation of cholesterol esters as analysis of islet gene expression reveals that LXRbeta is required for expression of the cholesterol transporters, ABCA1 and ABCG1. Our data establish novel roles for LXRbeta in adipocyte growth, glucose homeostasis, and beta cell function.     

Preserved glucose tolerance in high-fat-fed C57BL/6 mice transplanted with PPARgamma-/-, PPARdelta-/-, PPARgammadelta-/-, or LXRalphabeta-/- bone marrow

Macrophage lipid metabolism and inflammatory responses are both regulated by the nuclear receptors PPAR and LXR. Emerging links between inflammation and metabolic disease progression suggest that PPAR and LXR signaling may alter macrophage function and thereby impact systemic metabolism. In this study, the function of macrophage PPAR and LXR in Th1-biased C57BL/6 mice was tested using a bone marrow transplantation approach with PPARgamma(-/-), PPARdelta(-/-), PPARgammadelta(-/-), and LXRalphabeta(-/-) cells. Despite their inhibitory effects on inflammatory gene expression, loss of PPARs or LXRs in macrophages did not exert major effects on obesity or glucose tolerance induced by a high-fat diet. Treatment with rosiglitazone effectively improved glucose tolerance in mice lacking macrophage PPARgamma, suggesting that cell types other than macrophages are the primary mediators of the anti-diabetic effects of PPARgamma agonists in our model system. C57BL/6 macrophages lacking PPARs or LXRs exhibited normal expression of most alternative activation gene markers, indicating that macrophage alternative activation is not absolutely dependent on these receptors in the C57BL/6 background under the conditions used here. These studies suggest that genetic background may be an important modifier of nuclear receptor effects in macrophages. Our results do not exclude a contribution of macrophage PPAR and LXR expression to systemic metabolism in certain contexts, but these factors do not appear to be dominant contributors to glucose tolerance in a high-fat-fed Th1-biased bone marrow transplant model.     

母鼠营养不良导致子代在生命早期出现糖脂代谢紊乱及其机制探讨

为了探讨母鼠孕期和哺乳期营养不良对子代生命早期糖脂代谢的影响及其机制,文章对孕期和哺乳期母鼠分别喂养高脂饮食、低蛋白饮食和正常饮食,观察其子鼠断乳时(3周龄)糖脂代谢指标,并采用荧光定量PCR方法检测子鼠肝组织氧化物酶增殖物激活受体γ(PPARγ)基因的表达情况。结果表明：子鼠在3周龄时,与正常饮食组相比,低蛋白饮食组子鼠出生体重(7.36±0.91 vs 8.94±1.39,P<0.0001)较低,体长较短(12.27±0.53 vs 13.44±0.36,P<0.0001);高脂饮食组子鼠体重(9.53±0.68 vs 7.36±0.91,P<0.0001)和体长(13.22±0.35 vs 12.27±0.53,P<0.0001)均高于低蛋白饮食组;另外,高脂饮食组子鼠腹腔糖耐量实验30 min和60 min血糖明显高于正常饮食组(P<0.001),且高脂饮食组30 min血糖水平也明显高于低蛋白饮食组(P<0.001),高脂饮食组子鼠糖耐量曲线下面积明显大于正常饮食组(P<0.001)。另外,与正常饮食组相比,高脂饮食组子鼠空腹胆固醇水平明显升高(1.64±0.21 vs 1.18±0.16,P<0.01),低蛋白饮食组空腹胆固醇水平明显下降(0.96±0.09 vs 1.18±0.16,P<0.05)。荧光定量PCR结果显示,在低蛋白饮食组和高脂饮食组,其子鼠肝组织PPARγ基因表达量均明显高于正常饮食组(P<0.05)。结果显示,母鼠妊娠期和哺乳期高脂饮食与低蛋白饮食均可以诱导子鼠在发育早期出现糖脂代谢紊乱,PPARγ基因可能在其中参与了重要的调控作用。     

LXR-dependent gene expression is important for macrophage survival and the innate immune response

The liver X receptors (LXRs) are nuclear receptors with established roles in the regulation of lipid metabolism. We now show that LXR signaling not only regulates macrophage cholesterol metabolism but also impacts antimicrobial responses. Mice lacking LXRs are highly susceptible to infection with the intracellular bacteria Listeria monocytogenes (LM). Bone marrow transplant studies point to altered macrophage function as the major determinant of susceptibility. LXR-null macrophages undergo accelerated apoptosis when challenged with LM and exhibit defective bacterial clearance in vivo. These defects result, at least in part, from loss of regulation of the antiapoptotic factor SPalpha, a direct target for regulation by LXRalpha. Expression of LXRalpha or SPalpha in macrophages inhibits apoptosis in the setting of LM infection. Our results demonstrate that LXR-dependent gene expression plays an unexpected role in innate immunity and suggest that common nuclear receptor pathways mediate macrophage responses to modified lipoproteins and intracellular pathogens.     

LXR is crucial in lipid metabolism

Liver X receptors (LXRalpha and LXRbeta) are members of the nuclear receptor superfamily and are activated by oxysterols and intermediates in the cholesterol synthetic pathway. The pivotal role of LXRs in the metabolic conversion of cholesterol to bile acids is well established. Analysis of gene expression in LXRalpha and LXRbeta deficient mice have confirmed that LXR regulates a number of target genes involved in both cholesterol and fatty acid metabolism in liver, macrophages and intestine. The observation that LXRalpha is responsive to fatty acids and is expressed in metabolic tissues suggests that it also plays a general role in lipid metabolism. Adipose tissue is the main storage site for fat in the body and plays a crucial role in overall lipid handling. Both LXRalpha and LXRbeta are expressed and activated by endogenous and synthetic ligands, which lead to lipid accumulation into adipocytes. This indicates an important regulatory role of LXR in several metabolic signaling pathways in the adipose tissue, such as glucose uptake and de novo fatty acid synthesis. Here, we review recent studies that provide new insights into the mechanisms by which LXRs act to influence fatty acid synthesis in liver and adipose tissue.     

Antiproliferative Effects and Mechanisms of Liver X Receptor Ligands in Pancreatic Ductal Adenocarcinoma Cells

Pancreatic ductal adenocarcinoma (PDAC) is difficult to detect early and is often resistant to standard chemotherapeutic options, contributing to extremely poor disease outcomes. Members of the nuclear receptor superfamily carry out essential biological functions such as hormone signaling and are successfully targeted in the treatment of endocrine-related malignancies. Liver X receptors (LXRs) are nuclear receptors that regulate cholesterol homeostasis, lipid metabolism, and inflammation, and LXR agonists have been developed to regulate LXR function in these processes. Intriguingly, these compounds also exhibit antiproliferative activity in diverse types of cancer cells. In this study, LXR agonist treatments disrupted proliferation, cell-cycle progression, and colony-formation of PDAC cells. At the molecular level, treatments downregulated expression of proteins involved in cell cycle progression and growth factor signaling. Microarray experiments further revealed changes in expression profiles of multiple gene networks involved in biological processes and pathways essential for cell growth and proliferation following LXR activation. These results establish the antiproliferative effects of LXR agonists and potential mechanisms of action in PDAC cells and provide evidence for their potential application in the prevention and treatment of PDAC.     

Liver X receptor signaling pathways in cardiovascular disease

The liver X receptors alpha and beta (LXRalpha and LXRbeta) are members of the nuclear receptor family of proteins that are critical for the control of lipid homeostasis in vertebrates. The endogenous activators of these receptors are oxysterols and intermediates in the cholesterol biosynthetic pathway. LXRs serve as cholesterol sensors that regulate the expression of multiple genes involved in the efflux, transport, and excretion of cholesterol. Recent studies have outlined the importance of LXR signaling pathways in the development of metabolic disorders such as hyperlipidemia and atherosclerosis. Synthetic LXR agonists inhibit the development of atherosclerosis in murine models, an effect that is likely to result from the modulation of both metabolic and inflammatory gene expression. These observations identify the LXR pathway as a potential target for therapeutic intervention in human cardiovascular disease.