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1.
bioRxiv ; 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38798597

RESUMO

Liver x receptor alpha (LXRα, Nr1h3) functions as an important intracellular cholesterol sensor that regulates fat and cholesterol metabolism at the transcriptional level in response to the direct binding of cholesterol derivatives. We have generated mice with a mutation in LXRα that reduces activity in response to endogenous cholesterol derived LXR ligands while still allowing transcriptional activation by synthetic agonists. The mutant LXRα functions as a dominant negative that shuts down cholesterol sensing. When fed a high fat, high cholesterol diet LXRα mutant mice rapidly develop pathologies associated with Metabolic Dysfunction-Associated Steatohepatitis (MASH) including ballooning hepatocytes, liver inflammation, and fibrosis. Strikingly LXRα mutant mice have decreased liver triglycerides but increased liver cholesterol. Therefore, MASH-like phenotypes can arise in the absence of large increases in triglycerides. Reengaging LXR signaling by treatment with synthetic agonist reverses MASH suggesting that LXRα normally functions to impede the development of liver disease.

2.
ACS Chem Biol ; 17(5): 1143-1154, 2022 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-35417135

RESUMO

Hyperlipidemia and increased circulating cholesterol levels are associated with increased cardiovascular disease risk. The liver X receptors (LXRs) are regulators of de novo lipogenesis and cholesterol transport and have been validated as potential therapeutic targets for the treatment of atherosclerosis. However, efforts to develop LXR agonists to reduce cardiovascular diseases have failed due to poor clinical outcomes-associated increased hepatic lipogenesis and elevated low-density lipoprotein (LDL) cholesterol (C). Here, we report that LXR inverse agonists are effective in lowering plasma LDL cholesterol and triglycerides in several models of hyperlipidemia, including the Ldlr null mouse model of atherosclerosis. Mechanistic studies demonstrate that LXR directly regulates the expression of Soat2 enzyme in the intestine, which is directly responsible for the re-uptake or excretion of circulating lipids. Oral administration of a gut-specific LXR inverse agonist leads to reduction of Soat2 expression in the intestine and effectively lowers circulating LDL cholesterol and triglyceride levels without modulating LXR target genes in the periphery. In summary, our studies highlight the therapeutic potential of the gut-restricted molecules to treat hyperlipidemia and atherosclerosis through the intestinal LXR-Soat2 axis.


Assuntos
Aterosclerose , Receptores Nucleares Órfãos , Animais , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Colesterol/metabolismo , LDL-Colesterol/uso terapêutico , Hipolipemiantes/uso terapêutico , Receptores X do Fígado , Camundongos , Camundongos Endogâmicos C57BL , Receptores Nucleares Órfãos/agonistas , Receptores Nucleares Órfãos/genética , Receptores Nucleares Órfãos/metabolismo
3.
Biochim Biophys Acta Mol Basis Dis ; 1867(6): 166121, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33713792

RESUMO

The liver x receptors LXRα (NR1H3) and LXRß (NR1H2) are members of the nuclear hormone receptor superfamily of ligand dependent transcription factors that regulate transcription in response to the direct binding of cholesterol derivatives. Studies using genetic knockouts and synthetic ligands have defined the LXRs as important modulators of lipid homeostasis throughout the body. This review focuses on the control of cholesterol and fatty acid metabolism by LXRs in the liver and how modifying LXR activity can influence the pathology of liver diseases.


Assuntos
Colesterol/metabolismo , Homeostase , Metabolismo dos Lipídeos , Hepatopatias/fisiopatologia , Receptores X do Fígado/metabolismo , Animais , Humanos
4.
Mol Cell Biol ; 40(2)2020 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-31658997

RESUMO

Immune cell function can be modulated by changes in lipid metabolism. Our studies indicate that cholesterol and fatty acid synthesis increases in macrophages between 12 and 18 h after the activation of Toll-like receptors with proinflammatory stimuli and that the upregulation of lipogenesis may contribute to the resolution of inflammation. The inflammation-dependent increase in lipogenesis requires the induction of the liver X receptors, members of the nuclear receptor superfamily of transcription factors, by type I interferons in response to inflammatory signals. Instead of the well-established role for liver X receptors in stimulating cholesterol efflux, we demonstrate that liver X receptors are necessary for the proper resumption of cholesterol synthesis in response to inflammatory signals. Thus, liver X receptors function as bidirectional regulators of cholesterol homeostasis, driving efflux when cholesterol levels are high and facilitating synthesis in response to inflammatory signals. Liver X receptor activity is also required for the proper shutdown of a subset of type I interferon-stimulated genes as inflammation subsides, placing the receptors in a negative-feedback loop that may contribute to the resolution of the inflammatory response.


Assuntos
Colesterol/metabolismo , Inflamação/metabolismo , Lipogênese , Receptores X do Fígado/metabolismo , Animais , Linhagem Celular , Células Cultivadas , Células HEK293 , Humanos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL
5.
Commun Biol ; 2: 431, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31799433

RESUMO

Liver X receptors (LXRs) are attractive drug targets for cardiovascular disease treatment due to their role in regulating cholesterol homeostasis and immunity. The anti-atherogenic properties of LXRs have prompted development of synthetic ligands, but these cause major adverse effects-such as increased lipogenesis-which are challenging to dissect from their beneficial activities. Here we show that LXR compounds displaying diverse functional responses in animal models induce distinct receptor conformations. Combination of hydrogen/deuterium exchange mass spectrometry and multivariate analysis allowed identification of LXR regions differentially correlating with anti-atherogenic and lipogenic activities of ligands. We show that lipogenic compounds stabilize active states of LXRα and LXRß while the anti-atherogenic expression of the cholesterol transporter ABCA1 is associated with the ligand-induced stabilization of LXRα helix 3. Our data indicates that avoiding ligand interaction with the activation helix 12 while engaging helix 3 may provide directions for development of ligands with improved therapeutic profiles.


Assuntos
Receptores X do Fígado/química , Receptores X do Fígado/metabolismo , Modelos Moleculares , Conformação Proteica , Transportador 1 de Cassete de Ligação de ATP/química , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Descoberta de Drogas , Humanos , Ligantes , Estrutura Molecular , Correpressor 1 de Receptor Nuclear/química , Correpressor 1 de Receptor Nuclear/metabolismo , Ligação Proteica , Relação Estrutura-Atividade
6.
Arterioscler Thromb Vasc Biol ; 38(5): 1020-1029, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29599136

RESUMO

OBJECTIVE: Inflammatory macrophages promote the development of atherosclerosis. We have identified the adaptor protein Dab2 (disabled homolog 2) as a regulator of phenotypic polarization in macrophages. The absence of Dab2 in myeloid cells promotes an inflammatory phenotype, but the impact of myeloid Dab2 deficiency on atherosclerosis has not been shown. APPROACH AND RESULTS: To determine the role of myeloid Dab2 in atherosclerosis, Ldlr-/- mice were reconstituted with either Dab2-positive or Dab2-deficient bone marrow and fed a western diet. Consistent with our previous finding that Dab2 inhibits NFκB (nuclear factor κ-light-chain-enhancer of activated B cells) signaling in macrophages, Ldlr-/- mice reconstituted with Dab2-deficient bone marrow had increased systemic inflammation as evidenced by increased serum IL-6 (interleukin-6) levels and increased inflammatory cytokine expression levels in liver. Serum lipid levels were significantly lower in Ldlr-/- mice reconstituted with Dab2-deficient bone marrow, and further examination of livers from these mice revealed drastically increased inflammatory tissue damage and massive infiltration of immune cells. Surprisingly, the atherosclerotic lesion burden in Ldlr-/- mice reconstituted with Dab2-deficient bone marrow was decreased compared with Ldlr-/- mice reconstituted with wild-type bone marrow. Further analysis of aortic root sections revealed increased macrophage content and evidence of increased apoptosis in lesions from Ldlr-/- mice reconstituted with Dab2-deficient bone marrow but no difference in collagen or α-smooth muscle actin content. CONCLUSIONS: Dab2 deficiency in myeloid cells promotes inflammation in livers and atherosclerotic plaques in a mouse model of atherosclerosis. Nevertheless, decreased serum lipids as a result of massive inflammatory liver damage may preclude an appreciable increase in atherosclerotic lesion burden in mice reconstituted with Dab2-deficient bone marrow.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/deficiência , Aorta/metabolismo , Doenças da Aorta/metabolismo , Aterosclerose/metabolismo , Hepatite/metabolismo , Fígado/metabolismo , Macrófagos/metabolismo , Placa Aterosclerótica , Receptores de LDL/deficiência , Proteínas Adaptadoras de Transdução de Sinal , Proteínas Adaptadoras de Transporte Vesicular/genética , Animais , Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/patologia , Proteínas Reguladoras de Apoptose , Aterosclerose/genética , Aterosclerose/patologia , Caspases/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Progressão da Doença , Feminino , Hepatite/genética , Hepatite/patologia , Humanos , Interleucina-6/sangue , Células Jurkat , Lipídeos/sangue , Fígado/patologia , Macrófagos/patologia , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Fenótipo , Receptores de LDL/genética , Transdução de Sinais , Triglicerídeos/metabolismo
7.
Immunity ; 48(1): 75-90.e6, 2018 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-29343442

RESUMO

The molecular basis of signal-dependent transcriptional activation has been extensively studied in macrophage polarization, but our understanding remains limited regarding the molecular determinants of repression. Here we show that IL-4-activated STAT6 transcription factor is required for the direct transcriptional repression of a large number of genes during in vitro and in vivo alternative macrophage polarization. Repression results in decreased lineage-determining transcription factor, p300, and RNA polymerase II binding followed by reduced enhancer RNA expression, H3K27 acetylation, and chromatin accessibility. The repressor function of STAT6 is HDAC3 dependent on a subset of IL-4-repressed genes. In addition, STAT6-repressed enhancers show extensive overlap with the NF-κB p65 cistrome and exhibit decreased responsiveness to lipopolysaccharide after IL-4 stimulus on a subset of genes. As a consequence, macrophages exhibit diminished inflammasome activation, decreased IL-1ß production, and pyroptosis. Thus, the IL-4-STAT6 signaling pathway establishes an alternative polarization-specific epigenenomic signature resulting in dampened macrophage responsiveness to inflammatory stimuli.


Assuntos
Interleucina-4/metabolismo , Macrófagos/metabolismo , Fator de Transcrição STAT6/metabolismo , Animais , Western Blotting , Linhagem Celular , Elementos Facilitadores Genéticos , Citometria de Fluxo , Regulação da Expressão Gênica , Inflamassomos/metabolismo , Citometria de Varredura a Laser , Lipopolissacarídeos/farmacologia , Macrófagos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase , Piroptose/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
8.
FEBS Lett ; 591(19): 2978-2991, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28555747

RESUMO

The response of immune cells to pathogens is often associated with changes in the flux through basic metabolic pathways. Indeed, in many cases changes in metabolism appear to be necessary for a robust immune response. The Liver X receptors (LXRs) are members of the nuclear hormone receptor superfamily that regulate gene networks controlling cholesterol and lipid metabolism. In immune cells, particularly in macrophages, LXRs also inhibit proinflammatory gene expression. This Review will highlight recent studies that connect LXR-dependent control of lipid metabolism to regulation of the immune response.


Assuntos
Inflamação/metabolismo , Metabolismo dos Lipídeos , Receptores X do Fígado/metabolismo , Animais , DNA/metabolismo , Redes Reguladoras de Genes , Humanos , Inflamação/genética , Metabolismo dos Lipídeos/genética , Transcrição Gênica
9.
J Clin Invest ; 127(3): 1031-1045, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-28218622

RESUMO

Peptides derived from pre-proglucagon (GCG peptides) act in both the periphery and the CNS to change food intake, glucose homeostasis, and metabolic rate while playing a role in anxiety behaviors and physiological responses to stress. Although the actions of GCG peptides produced in the gut and pancreas are well described, the role of glutamatergic GGC peptide-secreting hindbrain neurons in regulating metabolic homeostasis has not been investigated. Here, we have shown that chemogenetic stimulation of GCG-producing neurons reduces metabolic rate and food intake in fed and fasted states and suppresses glucose production without an effect on glucose uptake. Stimulation of GCG neurons had no effect on corticosterone secretion, body weight, or conditioned taste aversion. In the diet-induced obese state, the effects of GCG neuronal stimulation on gluconeogenesis were lost, while the food intake-lowering effects remained, resulting in reductions in body weight and adiposity. Our work suggests that GCG peptide-expressing neurons can alter feeding, metabolic rate, and glucose production independent of their effects on hypothalamic pituitary-adrenal (HPA) axis activation, aversive conditioning, or insulin secretion. We conclude that GCG neurons likely stimulate separate populations of downstream cells to produce a change in food intake and glucose homeostasis and that these effects depend on the metabolic state of the animal.


Assuntos
Peso Corporal/fisiologia , Ingestão de Alimentos/fisiologia , Sistema Hipotálamo-Hipofisário/metabolismo , Neurônios/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Proglucagon/metabolismo , Animais , Gluconeogênese/genética , Camundongos , Camundongos Transgênicos , Proglucagon/genética , Rombencéfalo/metabolismo
10.
ACS Med Chem Lett ; 7(12): 1207-1212, 2016 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-27994765

RESUMO

Introducing a uniquely substituted phenyl sulfone into a series of biphenyl imidazole liver X receptor (LXR) agonists afforded a dramatic potency improvement for induction of ATP binding cassette transporters, ABCA1 and ABCG1, in human whole blood. The agonist series demonstrated robust LXRß activity (>70%) with low partial LXRα agonist activity (<25%) in cell assays, providing a window between desired blood cell ABCG1 gene induction in cynomolgus monkeys and modest elevation of plasma triglycerides for agonist 15. The addition of polarity to the phenyl sulfone also reduced binding to the plasma protein, human α-1-acid glycoprotein. Agonist 15 was selected for clinical development based on the favorable combination of in vitro properties, excellent pharmacokinetic parameters, and a favorable lipid profile.

11.
J Clin Invest ; 125(7): 2748-58, 2015 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-26075824

RESUMO

Macrophages clear millions of apoptotic cells daily and, during this process, take up large quantities of cholesterol. The membrane transporter ABCA1 is a key player in cholesterol efflux from macrophages and has been shown via human genetic studies to provide protection against cardiovascular disease. How the apoptotic cell clearance process is linked to macrophage ABCA1 expression is not known. Here, we identified a plasma membrane-initiated signaling pathway that drives a rapid upregulation of ABCA1 mRNA and protein. This pathway involves the phagocytic receptor brain-specific angiogenesis inhibitor 1 (BAI1), which recognizes phosphatidylserine on apoptotic cells, and the intracellular signaling intermediates engulfment cell motility 1 (ELMO1) and Rac1, as ABCA1 induction was attenuated in primary macrophages from mice lacking these molecules. Moreover, this apoptotic cell-initiated pathway functioned independently of the liver X receptor (LXR) sterol-sensing machinery that is known to regulate ABCA1 expression and cholesterol efflux. When placed on a high-fat diet, mice lacking BAI1 had increased numbers of apoptotic cells in their aortic roots, which correlated with altered lipid profiles. In contrast, macrophages from engineered mice with transgenic BAI1 overexpression showed greater ABCA1 induction in response to apoptotic cells compared with those from control animals. Collectively, these data identify a membrane-initiated pathway that is triggered by apoptotic cells to enhance ABCA1 within engulfing phagocytes and with functional consequences in vivo.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/biossíntese , Apoptose/fisiologia , Transportador 1 de Cassete de Ligação de ATP/deficiência , Transportador 1 de Cassete de Ligação de ATP/genética , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Angiogênicas/genética , Proteínas Angiogênicas/metabolismo , Animais , Membrana Celular/metabolismo , Colesterol/metabolismo , Feminino , Humanos , Células Jurkat , Metabolismo dos Lipídeos , Receptores X do Fígado , Macrófagos/citologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neuropeptídeos/deficiência , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Receptores Nucleares Órfãos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Regulação para Cima , Proteínas rac1 de Ligação ao GTP/deficiência , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/metabolismo
12.
Arterioscler Thromb Vasc Biol ; 34(8): 1650-60, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24947527

RESUMO

OBJECTIVE: The ability of high-density lipoprotein (HDL) particles to accept cholesterol from peripheral cells, such as lipid-laden macrophages, and to transport cholesterol to the liver for catabolism and excretion in a process termed reverse cholesterol transport (RCT) is thought to underlie the beneficial cardiovascular effects of elevated HDL. The liver X receptors (LXRs; LXRα and LXRß) regulate RCT by controlling the efflux of cholesterol from macrophages to HDL and the excretion, catabolism, and absorption of cholesterol in the liver and intestine. Importantly, treatment with LXR agonists increases RCT and decreases atherosclerosis in animal models. Nevertheless, LXRs are expressed in multiple tissues involved in RCT, and their tissue-specific contributions to RCT are still not well defined. APPROACH AND RESULTS: Using tissue-specific LXR deletions together with in vitro and in vivo assays of cholesterol efflux and fecal cholesterol excretion, we demonstrate that macrophage LXR activity is neither necessary nor sufficient for LXR agonist-stimulated RCT. In contrast, the ability of LXR agonists primarily acting in the intestine to increase HDL mass and HDL function seems to underlie the ability of LXR agonists to stimulate RCT in vivo. CONCLUSIONS: We demonstrate that activation of LXR in macrophages makes little or no contribution to LXR agonist-stimulated RCT. Unexpectedly, our studies suggest that the ability of macrophages to efflux cholesterol to HDL in vivo is not regulated by macrophage activity but is primarily determined by the quantity and functional activity of HDL.


Assuntos
Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Colesterol/metabolismo , Macrófagos/metabolismo , Receptores Nucleares Órfãos/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Transporte Biológico , Linhagem Celular , Colesterol/sangue , Proteínas de Transferência de Ésteres de Colesterol/genética , Colesterol na Dieta/metabolismo , HDL-Colesterol/metabolismo , Fezes/química , Humanos , Hidrocarbonetos Fluorados/farmacologia , Mucosa Intestinal/metabolismo , Fígado/metabolismo , Receptores X do Fígado , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptores Nucleares Órfãos/agonistas , Receptores Nucleares Órfãos/deficiência , Receptores Nucleares Órfãos/genética , Sulfonamidas/farmacologia , Fatores de Tempo
14.
Arterioscler Thromb Vasc Biol ; 33(6): 1120-6, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23640492

RESUMO

Macrophages orchestrate the inflammatory response in inflamed tissues, and recent work indicates that these cells can alter their phenotypes and functions accordingly in response to changes in the microenvironment. Initial work in models of cardiovascular disease used immunologic markers to characterize macrophage phenotypes present in atherosclerotic plaque, and these studies have lately been extended through the use of markers that are more specific for atherosclerosis and metabolic disease. Together, these studies have led to a novel view of the function of macrophages in the development of atherosclerosis that suggests dynamic plasticity. Understanding this plasticity and the ensuing macrophage heterogeneity could lead to novel strategies of pharmacological intervention to combat chronic inflammation in metabolic diseases. Most importantly, revealing the functional characteristics of individual macrophage phenotypes will lead to a better understanding of their contribution to lesion development and plaque stability.


Assuntos
Aterosclerose/genética , Inflamação/genética , Macrófagos/imunologia , Placa Aterosclerótica/genética , Aterosclerose/fisiopatologia , Progressão da Doença , Regulação da Expressão Gênica , Humanos , Inflamação/imunologia , Fenótipo , Placa Aterosclerótica/fisiopatologia , Fatores de Risco , Sensibilidade e Especificidade
15.
Mol Endocrinol ; 27(7): 1036-47, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23686114

RESUMO

The ability of cells to precisely control gene expression in response to intracellular and extracellular signals plays an important role in both normal physiology and in pathological settings. For instance, the accumulation of excess cholesterol by macrophages initiates a genetic response mediated by the liver X receptors (LXRs)-α (NR1H3) and LXRß (NR1H2), which facilitates the transport of cholesterol out of cells to high-density lipoprotein particles. Studies using synthetic LXR agonists have also demonstrated that macrophage LXR activation simultaneously induces a second network of genes that promotes fatty acid and triglyceride synthesis that may support the detoxification of excess free cholesterol by storage in the ester form. We now show that treatment of human THP-1 macrophages with endogenous or synthetic LXR ligands stimulates both transcriptional and posttranscriptional pathways that result in the selective recruitment of the LXRα subtype to LXR-regulated promoters. Interestingly, when human or mouse macrophages are loaded with cholesterol under conditions that mimic the development of atherogenic macrophage foam cells, a selective LXR response is generated that induces genes mediating cholesterol transport but does not coordinately regulate genes involved in fatty acid synthesis. The gene-selective response to cholesterol loading occurs, even in the presence of LXRα binding to the promoter of the gene encoding the sterol regulatory element-binding protein-1c, the master transcriptional regulator of fatty acid synthesis. The ability of promoter bound LXRα to recruit RNA polymerase to the sterol regulatory element-binding protein-1c promoter, however, appears to be ligand selective.


Assuntos
Colesterol/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Macrófagos/metabolismo , Receptores Nucleares Órfãos/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Animais , Linhagem Celular , Meia-Vida , Humanos , Ligantes , Receptores X do Fígado , Macrófagos/efeitos dos fármacos , Camundongos , Receptores Nucleares Órfãos/agonistas , Regiões Promotoras Genéticas/genética , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/genética , Elementos de Resposta/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
16.
J Clin Invest ; 122(5): 1688-99, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22484817

RESUMO

Liver X receptors (LXRα and LXRß) are important regulators of cholesterol and lipid metabolism, and their activation has been shown to inhibit cardiovascular disease and reduce atherosclerosis in animal models. Small molecule agonists of LXR activity are therefore of great therapeutic interest. However, the finding that such agonists also promote hepatic lipogenesis has led to the idea that hepatic LXR activity is undesirable from a therapeutic perspective. To investigate whether this might be true, we performed gene targeting to selectively delete LXRα in hepatocytes. Liver-specific deletion of LXRα in mice substantially decreased reverse cholesterol transport, cholesterol catabolism, and cholesterol excretion, revealing the essential importance of hepatic LXRα for whole body cholesterol homeostasis. Additionally, in a pro-atherogenic background, liver-specific deletion of LXRα increased atherosclerosis, uncovering an important function for hepatic LXR activity in limiting cardiovascular disease. Nevertheless, synthetic LXR agonists still elicited anti-atherogenic activity in the absence of hepatic LXRα, indicating that the ability of agonists to reduce cardiovascular disease did not require an increase in cholesterol excretion. Furthermore, when non-atherogenic mice were treated with synthetic LXR agonists, liver-specific deletion of LXRα eliminated the detrimental effect of increased plasma triglycerides, while the beneficial effect of increased plasma HDL was unaltered. In sum, these observations suggest that therapeutic strategies that bypass the liver or limit the activation of hepatic LXRs should still be beneficial for the treatment of cardiovascular disease.


Assuntos
Colesterol/metabolismo , Homeostase , Receptores Nucleares Órfãos/metabolismo , Animais , Anticolesterolemiantes/farmacologia , Anticolesterolemiantes/uso terapêutico , Aterosclerose/sangue , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Ácidos e Sais Biliares/biossíntese , Ácidos e Sais Biliares/metabolismo , Transporte Biológico , Células Cultivadas , Colesterol/sangue , Fezes/química , Feminino , Técnicas de Inativação de Genes , Hidrocarbonetos Fluorados/farmacologia , Hidrocarbonetos Fluorados/uso terapêutico , Metabolismo dos Lipídeos , Lipoproteínas/sangue , Lipoproteínas/metabolismo , Fígado/metabolismo , Receptores X do Fígado , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Especificidade de Órgãos , Receptores Nucleares Órfãos/agonistas , Receptores Nucleares Órfãos/genética , Tamanho da Partícula , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Triglicerídeos/sangue , Triglicerídeos/metabolismo
17.
J Theor Biol ; 290: 27-36, 2011 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-21884709

RESUMO

Liver toxicity (hepatotoxicity) is a critical issue in drug discovery and development. Standard preclinical evaluation of drug hepatotoxicity is generally performed using in vivo animal systems. However, only a small number of preselected compounds can be examined in vivo due to high experimental costs. A more efficient yet accurate screening technique that can identify potentially hepatotoxic compounds in the early stages of drug development would thus be valuable. Here, we develop and apply a novel genomic prediction technique for screening hepatotoxic compounds based on in vitro human liver cell tests. Using a training set of in vivo rodent experiments for drug hepatotoxicity evaluation, we discovered common biomarkers of drug-induced liver toxicity among six heterogeneous compounds. This gene set was further triaged to a subset of 32 genes that can be used as a multi-gene expression signature to predict hepatotoxicity. This multi-gene predictor was independently validated and showed consistently high prediction performance on five test sets of in vitro human liver cell and in vivo animal toxicity experiments. The predictor also demonstrated utility in evaluating different degrees of toxicity in response to drug concentrations, which may be useful not only for discerning a compound's general hepatotoxicity but also for determining its toxic concentration.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/genética , Avaliação Pré-Clínica de Medicamentos/métodos , Perfilação da Expressão Gênica/métodos , Fígado/efeitos dos fármacos , Algoritmos , Animais , Biomarcadores/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Humanos , Fígado/metabolismo , Fígado/patologia , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Valor Preditivo dos Testes , Ratos , Testes de Toxicidade/métodos , Toxicogenética/métodos
18.
Adv Drug Deliv Rev ; 62(13): 1307-15, 2010 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-20655343

RESUMO

Nuclear hormone receptors comprise a superfamily of ligand-activated transcription factors that control development, differentiation, and homeostasis. Over the last 15 years a growing number of nuclear receptors have been identified that coordinate genetic networks regulating lipid metabolism and energy utilization. Several of these receptors directly sample the levels of metabolic intermediates including fatty acids and cholesterol derivatives and use this information to regulate the synthesis, transport, and breakdown of the metabolite of interest. In contrast, other family members sense metabolic activity via the presence or absence of interacting proteins. The ability of these nuclear receptors to impact metabolism will be discussed and the challenges facing drug discovery efforts for this class of targets will be highlighted.


Assuntos
Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Terapia de Alvo Molecular , Receptores Nucleares Órfãos/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Descoberta de Drogas , Metabolismo Energético , Humanos , Ligantes , Metabolismo dos Lipídeos , Receptores X do Fígado , Neoplasias/induzido quimicamente , Receptores Nucleares Órfãos/agonistas , Receptores Nucleares Órfãos/genética , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores Ativados por Proliferador de Peroxissomo/genética , Receptores Citoplasmáticos e Nucleares/genética , Transdução de Sinais
19.
J Lipid Res ; 51(5): 900-6, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20388921

RESUMO

The liver X receptors LXRalpha and LXRbeta play critical roles in maintaining lipid homeostasis by functioning as transcription factors that regulate genetic networks controlling the transport, catabolism, and excretion of cholesterol. The studies described in this report examine the individual anti-atherogenic activity of LXRalpha and LXRbeta and determine the ability of each subtype to mediate the biological response to LXR agonists. Utilizing individual knockouts of LXRalpha and LXRbeta in the Ldlr(-/-) background, we demonstrate that LXRalpha has a dominant role in limiting atherosclerosis in vivo. Functional studies in macrophages indicate that LXRalpha is required for a robust response to LXR ligands, whereas LXRbeta functions more strongly as a repressor. Furthermore, selective knockout of LXRalpha in hematopoietic cells and rescue experiments indicate that the anti-atherogenic activity of this LXR subtype is not restricted to macrophages. These studies indicate that LXRalpha plays a selective role in limiting atherosclerosis in response to hyperlipidemia.


Assuntos
Aterosclerose/metabolismo , Técnicas de Inativação de Genes , Receptores Nucleares Órfãos/metabolismo , Receptores de LDL/deficiência , Receptores de LDL/genética , Animais , Células da Medula Óssea/metabolismo , Suscetibilidade a Doenças/metabolismo , Regulação da Expressão Gênica , Receptores X do Fígado , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Receptores Nucleares Órfãos/agonistas , Receptores Nucleares Órfãos/deficiência , Receptores Nucleares Órfãos/genética
20.
J Mol Cell Biol ; 1(2): 75-6, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19783832

RESUMO

The growing worldwide epidemic of cardiovascular disease suggests that new therapeutic strategies are needed to complement statins in the lowering of cholesterol levels. In a recent paper in Science, Tontonoz and colleagues have identified Idol as a protein that can control cholesterol levels by regulating the stability of the low-density lipoprotein receptor; inhibiting the activity of Idol could provide novel approaches for the treatment of cardiovascular disease.


Assuntos
Colesterol/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Fígado/metabolismo , Receptores X do Fígado , Camundongos , Receptores Nucleares Órfãos/metabolismo
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