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Liver X Receptor

Kaori Endo-Umeda, Hiroyuki Nakashima, Shihoko Komine-Aizawa, Naoki Umeda, Shuhji Seki, Makoto Makishima
The liver X receptors (LXRs), LXRα and LXRβ, are nuclear receptors that regulate lipid homeostasis. LXRs also regulate inflammatory responses in cultured macrophages. However, the role of LXRs in hepatic immune cells remains poorly characterized. We investigated the role of LXRs in regulation of inflammatory responses of hepatic mononuclear cells (MNCs) in mice. Both LXRα and LXRβ were expressed in mouse hepatic MNCs and F4/80+ Kupffer cells/macrophages. LXRα/β-knockout (KO) mice had an increased number of hepatic MNCs and elevated expression of macrophage surface markers and inflammatory cytokines compared to wild-type (WT) mice...
June 18, 2018: Scientific Reports
Jurjen Duintjer Tebbens, Malek Azar, Elfriede Friedmann, Martin Lanzendörfer, Petr Pávek
The pregnane X receptor (PXR) is a drug/xenobiotic-activated transcription factor of crucial importance for major cytochrome P450 xenobiotic-metabolizing enzymes (CYP) expression and regulation in the liver and the intestine. One of the major target genes regulated by PXR is the cytochrome P450 enzyme (CYP3A4), which is the most important human drug-metabolizing enzyme. In addition, PXR is supposed to be involved both in basal and/or inducible expression of many other CYPs, such as CYP2B6, CYP2C8, 2C9 and 2C19, CYP3A5, CYP3A7, and CYP2A6...
June 15, 2018: International Journal of Molecular Sciences
Matteo Tardelli, Thierry Claudel, Francesca Virginia Bruschi, Michael Trauner
Nuclear receptors, such as the farnesoid X receptor (FXR) and the peroxisome proliferator-activated receptors gamma and alpha (PPAR-γ, -α), are major metabolic regulators in adipose tissue and the liver, where they govern lipid, glucose, and bile acid homeostasis, as well as inflammatory cascades. Glycerol and free fatty acids are the end products of lipid droplet catabolism driven by PPARs. Aquaporins (AQPs), a family of 13 small transmembrane proteins, facilitate the shuttling of water, urea, and/or glycerol...
June 15, 2018: International Journal of Molecular Sciences
Pradeep K Shukla, Avtar S Meena, Bhargavi Manda, Maria Gomes-Solecki, Paula Dietrich, Ioannis Dragatsis, RadhaKrishna Rao
Pathogenesis of alcohol-related diseases such as alcoholic hepatitis involves gut barrier dysfunction, endotoxemia, and toxin-mediated cellular injury. Here we show that Lactobacillus plantarum not only blocks but also mitigates ethanol (EtOH)-induced gut and liver damage in mice. L. plantarum blocks EtOH-induced protein thiol oxidation, and down-regulation of antioxidant gene expression in colon L. plantarum also blocks EtOH-induced expression of TNF-α, IL-1β, IL-6, monocyte chemotactic protein 1 ( MCP1), C-X-C motif chemokine ligand ( CXCL)1, and CXCL2 genes in colon...
June 18, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Chuan-Chuan Wei, Zhi Luo, Christer Hogstrand, Yi-Huan Xu, Li-Xiang Wu, Guang-Hui Chen, Ya-Xiong Pan, Yu-Feng Song
Zinc (Zn) deficiency is the most consistently discovered nutritional manifestations of fatty liver disease. Although Zn is known to stimulate hepatic lipid oxidation, little is known about its underlying mechanism of action in lipolysis. Given the potential role of lipophagy in lipid metabolism, the purpose of this study was to test the hypothesis that Zn attenuates hepatic lipid accumulation by modulating lipophagy. The present study indicated that Zn is a potent promoter of lipophagy. Zn administration significantly alleviated hepatocellular lipid accumulation and increased the release of free fatty acids in association with enhanced fatty acid oxidation and inhibited lipogenesis, which was accompanied by activation of autophagy...
June 18, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Cancan Zhou, Zhenyan Gao, Ju Wang, Meiqin Wu, Shuang Hu, Fei Chen, Junxia Liu, Hui Pan, Chonghuai Yan
Lead exposure has been evidenced as a risk factor for Alzheimer's disease (AD), mainly affecting the ageing. However, the early manifestation and mechanisms of AD-like pathology induced by lead exposure remains to be elucidated. Considering the fact that impaired cholesterol metabolism is associated with many neurodegenerative disorders including AD, in this study we focused on the role of cholesterol metabolism in lead induced premature AD-like pathology. We treated weaning rats with lead at different concentrations for 4 weeks...
June 14, 2018: Toxicology Letters
Linlin Yan, Zhanfei Chen, Luxi Wu, Yongfa Su, Xiaoqian Wang, Nanhong Tang
Pregnane X Receptor (PXR), a nuclear receptor transcription factor, participates in a wide range of physiological activities, but the regulation of ammonia-induced hepatocyte autophagy by PXR is not yet clear. In this study, the levels of down-regulated LC3B-II and up-regulated SQSTM1 were found in ammonia-induced PXR-overexpressing (PXR+) liver cells, but the opposite appeared in PXR-knockdown (PXR-) liver cells. Rifampicin, a PXR-activating agent, elicits a similar effect as PXR + cells. The mechanism analysis reveals that the levels of the energy-sensitive molecule AMPKβ1 and phosphorylated AMPKβ1 (p-AMPKβ1) in PXR - cells are higher than those in control cells, whereas the levels of this molecule in PXR + cells are lower than those in control cells...
June 13, 2018: Toxicology Letters
Yuting Gu, Weiting Wei, Yiji Cheng, Bing Wan, Xinyuan Ding, Hui Wang, Yanyun Zhang, Min Jin
BACKGROUND: The activation and expansion of bipotent liver progenitor cells (LPCs) are indispensable for liver regeneration after severe or chronic liver injury. However, the underlying molecular mechanisms regulating LPCs and LPC-mediated liver regeneration remain elusive. METHODS: Hepatic brain-expressed X-linked 1 (BEX1) expression was evaluated using microarray screening, real-time polymerase chain reaction, immunoblotting and immunofluorescence. LPC activation and liver injury were studied following a choline-deficient, ethionine-supplemented (CDE) diet in wild-type (WT) and Bex1-/- mice...
June 15, 2018: Stem Cell Research & Therapy
Jarrod Sonett, Monica Goldklang, Piotr Sklepkiewicz, Adam Gerber, Jordis Trischler, Tina Zelonina, Marit Westerterp, Vincent Lemaître, Yasunori Okada, Jeanine D'Armiento
Macrophage infiltration is common to both emphysema and atherosclerosis, and cigarette smoke down-regulates the macrophage cholesterol efflux transporter ATP binding cassette (ABC)A1. This decreased cholesterol efflux results in lipid-laden macrophages. We hypothesize that cigarette smoke adversely affects cholesterol transport via an ABCA1-dependent mechanism in macrophages, enhancing TLR4/myeloid differentiation primary response gene 88 (Myd88) signaling and resulting in matrix metalloproteinase (MMP) up-regulation and exacerbation of pulmonary inflammation...
June 15, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Bo Wang, Peter Tontonoz
Liver X receptors α and β (LXRα and LXRβ) are nuclear receptors with pivotal roles in the transcriptional control of lipid metabolism. Transcriptional activity of LXRs is induced in response to elevated cellular levels of cholesterol. LXRs bind to and regulate the expression of genes that encode proteins involved in cholesterol absorption, transport, efflux, excretion and conversion to bile acids. The coordinated, tissue-specific actions of the LXR pathway maintain systemic cholesterol homeostasis and regulate immune and inflammatory responses...
June 14, 2018: Nature Reviews. Endocrinology
Yujie Liu, An Song, Xi Yang, Yunfeng Zhen, Weiwei Chen, Linquan Yang, Chao Wang, Huijuan Ma
The development of type‑2 diabetes and its complications is associated with lipid metabolism disorder. Farnesoid X receptor (FXR) has an important role in regulating lipid and glucose metabolism. However, the underlying mechanism of this remains unclear. The present study investigated the role of fexaramine (Fex), an FXR agonist, on lipid metabolism. For this purpose, 6‑week‑old db/db mice were treated with Fex for 8 weeks via oral gavage and db/db mice treated with corn oil were used as controls. Body weight and food intake were monitored daily and bi‑weekly, respectively...
June 5, 2018: International Journal of Molecular Medicine
Prasant Kumar Jena, Lili Sheng, Nidhi Nagar, Chao Wu, Daniela Barile, David A Mills, Yui-Jui Yvonne Wan
Probiotic Bifidobacterium longum subspecies infantis ( Bifidobacterium infantis ) consumes human milk oligosaccharides (MO) and protects intestinal permeability thereby having anti-inflammatory effects (Underwood et al., 2015; Bode, 2006; Asakuma et al., 2011) [1-3]. Via the gut-liver axis, gut barrier disruption and dysbiosis lead to hepatic inflammation (Sheng et al., 2017; Jena et al., 2017) [4,5,6]. Our published data revealed that butyrate, as well as synbiotics of B. infantis in combination with MO, had protective effects against cancer-prone non-alcoholic steatohepatitis (NASH) mouse models, i...
August 2018: Data in Brief
Sumihiko Hagita, Maximillian A Rogers, Tan Pham, Jennifer R Wen, Andrew K Mlynarchik, Masanori Aikawa, Elena Aikawa
The sorting receptor Sortilin functions in the regulation of glucose and lipid metabolism. Dysfunctional lipid uptake, storage, and metabolism contribute to several major human diseases including atherosclerosis and obesity. Sortilin associates with cardiovascular disease; however, the role of Sortilin in adipose tissue and lipid metabolism remains unclear. Here we show that in the low-density lipoprotein receptor-deficient (Ldlr-/- ) atherosclerosis model, Sortilin deficiency (Sort1-/- ) in female mice suppresses Niemann-Pick type C1-Like 1 (Npc1l1) mRNA levels, reduces body and white adipose tissue weight, and improves brown adipose tissue function partially via transcriptional downregulation of Krüppel-like factor 4 and Liver X receptor...
June 13, 2018: Scientific Reports
Lile Dong, Xu Han, Xufeng Tao, Lina Xu, Youwei Xu, Linlin Fang, Lianhong Yin, Yan Qi, Hua Li, Jinyong Peng
We previously reported the effects of the total flavonoids (TFs) from Rosa laevigata Michx fruit against carbon tetrachloride-induced liver damage, non-alcoholic fatty liver disease, and liver ischemia-reperfusion injury. However, there have been no papers reporting the role of R. laevigata TFs against lipopolysaccharide (LPS)-induced liver injury. In this paper, liver injury in mice was induced by LPS, and R. Laevigata extract was intragastrically administered to the mice for 7 days. Biochemical parameters in serum and liver tissue were examined, and pathological changes were observed by transmission electron microscopy, hematoxylin and eosin (H&E) and Oil Red O staining...
June 8, 2018: Foods (Basel, Switzerland)
Sonomi Maruyama, Chia-Ling Wu, Sumiko Yoshida, Dongying Zhang, Pei-Hsuan Li, Fangzhou Wu, Jennifer Parker Duffen, Rouan Yao, Blake Jardin, Ibrahim M Adham, Ronald Law, Joel Berger, Richard Di Marchi, Kenneth Walsh
BACKGROUND: The insulin/insulin-like growth factor/relaxin family represents a group of structurally related but functionally diverse proteins. The family member relaxin-2 has been evaluated in clinical trials for its efficacy in the treatment of acute heart failure. In this study, we assessed the role of insulin-like peptide 6 (INSL6), another member of this protein family, in murine heart failure models using genetic loss-of-function and protein delivery methods. METHODS AND RESULTS: Insl6-deficient and wild-type (C57BL/6N) mice were administered angiotensin II or isoproterenol via continuous infusion with an osmotic pump or via intraperitoneal injection once a day, respectively, for 2 weeks...
June 10, 2018: Journal of the American Heart Association
Shuqi Pu, Xiaojie Wu, Xiaoying Yang, Yunzhan Zhang, Yunkai Dai, Yueling Zhang, Xiaoting Wu, Yan Liu, Xiaona Cui, Haiyong Jin, Jianhong Cao, Ruliu Li, Jiazhong Cai, Qizhi Cao, Ling Hu, Yong Gao
Xenobiotic nuclear receptors (XNRs) are nuclear receptors that characterized by coordinately regulating the expression of genes encoding drug-metabolizing enzymes and transporters to essentially eliminate and detoxify xenobiotics and endobiotics from the body, including the peroxisome proliferator-activated receptor (PPAR), the farnesoid X receptor (FXR), the liver X receptor (LXR), the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR). Heretofore, increasing evidences have suggested that these five XNRs are not only involved in the regulation of xeno-/endo-biotics detoxication but also the development of human diseases, such as cancer, obesity and diabetes...
June 10, 2018: Current Drug Metabolism
Lili Sheng, Prasant Kumar Jena, Hui-Xin Liu, Ying Hu, Nidhi Nagar, Denise N Bronner, Matthew L Settles, Andreas J Bäumler, Yu-Jui Yvonne Wan
Dysregulated bile acid (BA) synthesis is accompanied by dysbiosis, leading to compromised metabolism. This study analyzes the effect of epigallocatechin-3-gallate (EGCG) on diet-induced obesity through regulation of BA signaling and gut microbiota. The data revealed that EGCG effectively reduced diet-increased obesity, visceral fat, and insulin resistance. Gene profiling data showed that EGCG had a significant impact on regulating genes implicated in fatty acid uptake, adipogenesis, and metabolism in the adipose tissue...
June 8, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Weiyang He, Shaojun Ye, Cheng Zeng, Shuai Xue, Xiaoyan Hu, Xingjian Zhang, Siqi Gao, Yan Xiong, Xueyu He, Soatina Vivalda, Ling Li, Yanfeng Wang, Qifa Ye
Hypothermic oxygenated perfusion (HOPE) is a relatively new dynamic preservation procedure that has not been widely implemented in liver transplantation despite its advantages. Improved graft protection is one such advantage offered by HOPE and has been attributed to multiple mechanisms, one of which may be the modulation of the thioredoxin-interacting protein (TXNIP)/NOD-like receptor protein 3 (NLRP3) inflammasome pathway. The TXNIP/NLRP3 inflammasome pathway plays a critical role in sterile inflammation under oxidative stress as a result of ischemia/reperfusion injury (IRI)...
June 5, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Qing-Zhi Liu, Wen-Tao Ma, Jing-Bo Yang, Zhi-Bin Zhao, Kai Yan, Yuan Yao, Liang Li, Qi Miao, M Eric Gershwin, Zhe-Xiong Lian
CXC chemokine receptor 3 (CXCR3), a receptor for the C-X-C motif chemokines (CXCL) CXCL9, CXCL10, and CXCL11, which not only plays a role in chemotaxis but also regulates differentiation and development of memory and effector T cell populations. Herein, we explored the function of CXCR3 in the modulation of different organ-specific autoimmune diseases in interleukin (IL)-2 receptor deficiency (CD25-/- ) mice, a murine model for both cholangitis and colitis. We observed higher levels of CXCL9 and CXCL10 in the liver and colon and higher expression of CXCR3 on T cells of the CD25-/- mice compared with control animals...
2018: Frontiers in Immunology
Rongya Tao, Caixia Wang, Oliver Stöhr, Wei Qiu, Yue Hu, Ji Miao, X Charlie Dong, Sining Leng, Margaret Stefater, Nicholas Stylopoulos, Lin Lin, Kyle D Copps, Morris F White
Unsuppressed hepatic glucose production (HGP) contributes substantially to glucose intolerance and diabetes, which can be modeled by the genetic inactivation of hepatic insulin receptor substrate 1 (Irs1) and Irs2 (LDKO mice). We previously showed that glucose intolerance in LDKO mice is resolved by hepatic inactivation of the transcription factor FoxO1 (that is, LTKO mice)-even though the liver remains insensitive to insulin. Here, we report that insulin sensitivity in the white adipose tissue of LDKO mice is also impaired but is restored in LTKO mice in conjunction with normal suppression of HGP by insulin...
June 4, 2018: Nature Medicine
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