Hepatic cholesterol metabolism and resistance to dietary cholesterol in LXRβ-deficient mice

Alberti, Siegfried; Schuster, Gertrud U.; Parini, Paolo; Feltkamp, Dorothee; Diczfalusy, Ulf; Rudling, Mats; Angelin, Bo; Björkhem, Ingemar; Pettersson, Sven; Gustafsson, Jan‐Åke

doi:10.1172/jci9794

Cited by 333 publications

(270 citation statements)

References 51 publications

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“…Both LXR a and LXR b are expressed in tissues such as the liver but have selective functions [Peet et al, 1998b;Alberti et al, 2001]. LXR a and LXR b share 78% amino acid sequence similarity in their DNA and LBDs, both bind DNA as heterodimer with the receptor RXR, and both bind preferentially to DR-4 response elements (LXRE) [Willy et al, 1995].…”

Section: Discussionmentioning

confidence: 99%

“…Both LXR a and LXR b regulate expression of gene products for transport, de novo synthesis, and catabolism of cholesterol [Peet et al, 1998b;Alberti et al, 2001;Stulnig et al, 2002], and for lipogenesis [Laffitte et al, 2003]. LXR a and LXR b belong to the type II family of nuclear receptors.…”

mentioning

confidence: 99%

“…Whereas knockout of LXR a in mice inhibited expression of lipogenic genes encoding steroyl coenzyme A desaturase 1 and fatty acid synthase, knockout of LXR b in mice did not affect expression of these genes [Alberti et al, 2001]. Instead, knockout of LXR b increased expression of another lipogenic gene, encoding acetyl CoA carboxylase [Alberti et al, 2001] and of the key regulator of lipogenic genes, sterol regulatory element binding protein-1 (SREBP-1) . Such increases in gene expression indicate a repressive effect of LXR b on these genes.…”

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confidence: 99%

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Nuclear localization of liver X receptor α and β is differentially regulated

Prüfer

Boudreaux

2006

J of Cellular Biochemistry

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Activity of nuclear receptors is regulated by their nuclear localization. Liver X receptors (LXR) a and b are nuclear receptors that regulate transcription of genes for cholesterol metabolism, cholesterol transport, and lipogenesis. While LXR a and b are very similar in structure and exhibit similar ligand binding properties, their physiological roles are quite different. Since the LXRs fall into a class of receptors that move between the nucleus and cytoplasm, experiments were conducted to determine whether LXR a and LXR b show differences in their nuclear localization pattern. To determine the location of each receptor, cell lines stably expressing yellow fluorescent protein (YFP) chimeras with either LXR a or LXR b were examined. Retention in the nucleus of the chimeric proteins in the presence or absence of ligands was assessed using fluorescence microscopy coupled with digitonin permeabilization assays. Surprisingly, differences were found between LXR a and LXR b. Whereas unliganded LXR a was retained in the nucleus, unliganded LXR b was partially exported. Mutations were then introduced into putative nuclear localization sequences (NLS) to determine which sequences are important for nuclear localization and function. Mutation in one such sequence abolished nuclear localization of LXR a, whereas the analogous change in LXR b had a much less dramatic effect. Mutations in analogous putative NLS also differentially affected transcriptional activation by LXR a and LXR b. These data demonstrate for the first time that nuclear retention and localization as well as function of LXR a and LXR b are differentially regulated.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Nuclear localization of liver X receptor α and β is differentially regulated

Prüfer

Boudreaux

2006

J of Cellular Biochemistry

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“…In contrast, LXR mice are relatively normal. Yet double knockout mice (LXR -/-, -/-) have a greater accumulation of cholesterol, suggesting some functional overlap (Alberti et al 2001). Pharmacologic activation of LXRs activates lipogenic genes, sterol regulatory element binding protein 1c, SREBP-1c; fatty acid synthase, FAS; and steroyl-CoA desaturase 1, SCD-1-and elevates both hepatic and plasma triglyceride levels (Peet et al 1998;Schultz et al 2000).…”

Section: Lxrsmentioning

confidence: 99%

Nuclear receptors, mitochondria and lipid metabolism

2008

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Lipid metabolism is a continuum from emulsification and uptake of lipids in the intestine to cellular uptake and transport to compartments such as mitochondria. Whether fats are shuttled into lipid droplets in adipose tissue or oxidized in mitochondria and peroxisomes depends on metabolic substrate availability, energy balance and endocrine signaling of the organism. Several members of the nuclear hormone receptor superfamily are lipid-sensing factors that affect all aspects of lipid metabolism. The physiologic actions of glandular hormones (e.g. thyroid, mineralocorticoid and glucocorticoid), vitamins (e.g. vitamins A and D) and reproductive hormones (e.g. progesterone, estrogen and testosterone) and their cognate receptors are well established. The peroxisome proliferator activated receptors (PPARs) and Liver X receptors (LXRs), acting in concert with PPARγ Coactivator 1α (PGC-1α), have been shown to regulate insulin sensitivity and lipid handling. These receptors are the focus of intense pharmacologic studies to expand the armamentarium of small molecule ligands to treat diabetes and the metabolic syndrome (hypertension, insulin resistance, hyperglycemia, dyslipidemia, and obesity). Recently, additional partners of PGC-1α have moved to the forefront of metabolic research, the Estrogen-related Receptors (ERRs). Although no endogenous ligands for these receptors have been identified, phenotypic analyses of knockout mouse models demonstrate an important role for these molecules in substrate sensing and handling as well as mitochondrial function.

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“…1 It is generally believed that the two isoforms can compensate for each other in biological activity. 3,4 Ligand activation of the LXRs decreases intestinal cholesterol absorption efficiency, induces cholesterol efflux from lipidladen macrophages and negatively regulates inflammatory gene expression, suggesting a beneficial effect on the development of cardiovascular disease. Direct evidence for a role of the LXR pathway in atherosclerosis susceptibility has been obtained from studies using genetically modified mice.…”

Section: Introductionmentioning

confidence: 99%

Macrophage LXRα gene therapy ameliorates atherosclerosis as well as hypertriglyceridemia in LDLR−/− mice

Biju

Xu³

et al. 2011

Gene Ther

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Liver X receptors (LXRs) are implicated in the regulation of cholesterol homeostasis, inflammatory response and atherogenesis. Administration of LXR agonists inhibits the progress of atherosclerosis, and also increases plasma triglyceride levels, representing an obstacle to their use in treating this disease. The objective of this study was to develop an alternative approach that could overcome this obstacle. Eight-week-old low-density lipoprotein receptor-deficient (LDLR À/À ) mice were transplanted with hematopoietic stem cell (HSC)-enriched bone marrow cells transduced with lentivectors expressing either green fluorescent protein (GFP) (Lenti-SP-GFP, control) or LXRa (Lenti-SP-LXRa) driven by a synthetic macrophage promoter. At 4 weeks post-transplant, the mice were fed with a Western diet for 8 weeks and then killed. Compared with Lenti-SP-GFP mice, the Lenti-SP-LXRa mice had a 30% reduction in atherosclerotic lesions, which was accompanied by increases in levels of macrophage expression of cholesterol efflux genes apolipoprotein E and ATP-binding cassette A1, as well as decreases in plasma inflammatory cytokines interleukin-6 and tumor necrosis factor-a. Intriguingly, a 50% reduction of plasma triglyceride level was also observed. We conclude that HSC-based macrophage LXRa gene therapy ameliorates the development of atherosclerosis along with an unexpected concomitant reduction of plasma triglyceride levels in LDLR À/À mice. These findings highlight the potential value of macrophage LXR expression as an avenue for therapeutic intervention against atherosclerosis.

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Hepatic cholesterol metabolism and resistance to dietary cholesterol in LXRβ-deficient mice

Cited by 333 publications

References 51 publications

Nuclear localization of liver X receptor α and β is differentially regulated

Nuclear localization of liver X receptor α and β is differentially regulated

Nuclear receptors, mitochondria and lipid metabolism

Macrophage LXRα gene therapy ameliorates atherosclerosis as well as hypertriglyceridemia in LDLR−/− mice

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