Publications by authors named "Chaitra Marathe"

7 Publications

  • Page 1 of 1

Restoration of euglycemia after duodenal bypass surgery is reliant on central and peripheral inputs in Zucker fa/fa rats.

Diabetes 2013 Apr 17;62(4):1074-83. Epub 2012 Dec 17.

NGM Biopharmaceuticals, Inc, South San Francisco, California, USA.

Gastrointestinal bypass surgeries that result in rerouting and subsequent exclusion of nutrients from the duodenum appear to rapidly alleviate hyperglycemia and hyperinsulinemia independent of weight loss. While the mechanism(s) responsible for normalization of glucose homeostasis remains to be fully elucidated, this rapid normalization coupled with the well-known effects of vagal inputs into glucose homeostasis suggests a neurohormonally mediated mechanism. Our results show that duodenal bypass surgery on obese, insulin-resistant Zucker fa/fa rats restored insulin sensitivity in both liver and peripheral tissues independent of body weight. Restoration of normoglycemia was attributable to an enhancement in key insulin-signaling molecules, including insulin receptor substrate-2, and substrate metabolism through a multifaceted mechanism involving activation of AMP-activated protein kinase and downregulation of key regulatory genes involved in both lipid and glucose metabolism. Importantly, while central nervous system-derived vagal nerves were not essential for restoration of insulin sensitivity, rapid normalization in hepatic gluconeogenic capacity and basal hepatic glucose production required intact vagal innervation. Lastly, duodenal bypass surgery selectively altered the tissue concentration of intestinally derived glucoregulatory hormone peptides in a segment-specific manner. The present data highlight and support the significance of vagal inputs and intestinal hormone peptides toward normalization of glucose and lipid homeostasis after duodenal bypass surgery.
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http://dx.doi.org/10.2337/db12-0681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3609588PMC
April 2013

Constitutive activation of LXR in macrophages regulates metabolic and inflammatory gene expression: identification of ARL7 as a direct target.

J Lipid Res 2011 Mar 27;52(3):531-9. Epub 2010 Dec 27.

Howard Hughes Medical Institute, Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, CA, USA.

Ligand activation of liver X receptors (LXRs) has been shown to impact both lipid metabolism and inflammation. One complicating factor in studies utilizing synthetic LXR agonists is the potential for pharmacologic and receptor-independent effects. Here, we describe an LXR gain-of-function system that does not depend on the addition of exogenous ligand. We generated transgenic mice expressing a constitutively active VP16-LXRα protein from the aP2 promoter. These mice exhibit increased LXR signaling selectively in adipose and macrophages. Analysis of gene expression in primary macrophages derived from two independent VP16-LXRα transgenic lines confirmed the ability of LXR to drive expression of genes involved in cholesterol efflux and fatty acid synthesis. Moreover, VP16-LXRα expression also suppressed the induction of inflammatory genes by lipopolysaccharide to a comparable degree as synthetic agonist. We further utilized VP16-LXRα-expressing macrophages to identify and validate new targets for LXRs, including the gene encoding ADP-ribosylation factor-like 7 (ARL7). ARL7 has previously been shown to transport cholesterol to the membrane for ABCA1-associated removal and thus may be integral to the LXR-dependent efflux pathway. We show that the ARL7 promoter contains a functional LXRE and can be transactivated by LXRs in a sequence-specific manner, indicating that ARL7 is a direct target of LXR. These findings provide further support for an important role of LXRs in the coordinated regulation of lipid metabolic and inflammatory gene programs in macrophages.
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http://dx.doi.org/10.1194/jlr.M010686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3035689PMC
March 2011

LXR deficiency confers increased protection against visceral Leishmania infection in mice.

PLoS Negl Trop Dis 2010 Nov 16;4(11):e886. Epub 2010 Nov 16.

Department of Medicine, Division of Dermatology and Infectious Diseases, Harbor-University of California Los Angeles Medical Center and Los Angeles Biomedical Research Institute, Torrance, California, USA.

Background: The liver X receptors (LXRs) are a family of nuclear receptor transcription factors that are activated by oxysterols and have defined roles in both lipid metabolism and cholesterol regulation. LXRs also affect antimicrobial responses and have anti-inflammatory effects in macrophages. As mice lacking LXRs are more susceptible to infection by intracellular bacteria Listeria monocytogenes and Mycobacterium tuberculosis, we hypothesized that LXR might also influence macrophage responses to the intracellular protozoan parasite Leishmania chagasi/infantum, a causative agent of visceral leishmaniasis.

Methods And Findings: Surprisingly, both LXRα knock-out and LXRα/LXRβ double-knock-out (DKO) mice were markedly resistant to systemic L. chagasi/infantum infection compared to wild-type mice. Parasite loads in the livers and spleens of these animals were significantly lower than in wild-type mice 28 days after challenge. Bone marrow-derived macrophages from LXR-DKO mice infected with L. chagasi/infantum in vitro in the presence of IFN-γ were able to kill parasites more efficiently than wild-type macrophages. This enhanced killing by LXR-deficient macrophages correlated with higher levels of nitric oxide produced, as well as increased gene expression of IL-1β. Additionally, LXR ligands abrogated nitric oxide production in wild-type macrophages in response to infection.

Conclusions: These observations suggest that LXR-deficient mice and macrophages mount antimicrobial responses to Leishmania infection that are distinct from those mounted by wild-type mice and macrophages. Furthermore, comparison of these findings to other intracellular infection models suggests that LXR signaling pathways modulate host antimicrobial responses in a complex and pathogen-specific manner. The LXR pathway thus represents a potential therapeutic target for modulating immunity against Leishmania or other intracellular parasites.
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http://dx.doi.org/10.1371/journal.pntd.0000886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2982826PMC
November 2010

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

J Lipid Res 2009 Feb 4;50(2):214-24. Epub 2008 Sep 4.

Howard Hughes Medical Institute, Molecular Biology Institute and Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095, USA.

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.
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http://dx.doi.org/10.1194/jlr.M800189-JLR200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2636915PMC
February 2009

Arginase I induction by modified lipoproteins in macrophages: a peroxisome proliferator-activated receptor-gamma/delta-mediated effect that links lipid metabolism and immunity.

Mol Endocrinol 2008 Jun 6;22(6):1394-402. Epub 2008 Mar 6.

Departamento de Bioquímica y Biología Molecular y Genética, Universidad de Extremadura. Avenida de la Universidad s/n, 10071 Cáceres, Spain.

Macrophages are phagocytic cells that play essential roles in innate immunity and lipid homeostasis. The uptake of modified lipoproteins is an important early event in the development of atherosclerosis. We analyzed the ability of modified low-density lipoprotein (LDL) (oxidized and acetylated) to alter the expression and activity of arginases (ArgI and ArgII) in macrophages. We show that ArgI expression is potently induced by both oxidized and acetylated LDL in macrophages. We further show that this effect is mediated by peroxisome proliferator-activated receptors (PPAR). ArgI expression is highly responsive to agonists for PPARgamma and PPARdelta but not PPARalpha. Moreover, the induction of ArgI by both PPAR agonists and IL-4 is blocked in macrophages from PPARgamma- and PPARdelta-deficient mice. Functionally, PPAR activity induces macrophage activation toward a more Th2 immune phenotype in a model of Leishmania major infection. We show that PPARgamma and -delta ligands promote intracellular amastigote growth in infected macrophages, and this effect is dependent on both PPAR expression and Arg activity. Collectively, our results strongly suggest that ArgI is a key marker of the alternative program triggered by PPAR in macrophages.
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http://dx.doi.org/10.1210/me.2007-0525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5419540PMC
June 2008

The arginase II gene is an anti-inflammatory target of liver X receptor in macrophages.

J Biol Chem 2006 Oct 30;281(43):32197-206. Epub 2006 Aug 30.

Howard Hughes Medical Institute, Molecular Biology Institute and Department of Pathology and Laboratory Medicine, University of California-Los Angeles, Los Angeles, CA 90095, USA.

The liver X receptors (LXRs) are ligand-dependent transcription factors that have been implicated in lipid metabolism and inflammation. LXRs also inhibit the expression of inflammatory genes in macrophages, including inducible nitric oxide synthase (iNOS). Some of these actions are mediated through LXR antagonism of NF-kappaB activity. The potential for LXRs to positively regulate the expression of anti-inflammatory molecules, however, has not been explored. Here we show that the arginase II (ArgII) gene is a direct target for LXR regulation. ArgII catalyzes the conversion of L-arginine into L-ornithine and urea, leading to the synthesis of polyamines. Expression of ArgII is induced by LXR agonists in macrophage cell lines and primary murine macrophages in a receptor-dependent manner. The ArgII promoter contains a functional LXR response elements that mediates promoter induction by LXR/RXR (retinoid X receptor) in transfection assays. Since ArgII and iNOS utilize a common substrate, induction of ArgII expression has the potential to exert anti-inflammatory effects by shifting arginine metabolism toward polyamine synthesis at the expense of NO production. In support of this hypothesis, we demonstrate that forced expression of ArgII mimics the inhibitory effect of LXR activation on macrophage NO production. Furthermore, inhibition of arginase activity partially reverses the inhibitory effect of LXR agonists on NO production. These studies suggest that regulation of ArgII may contribute to the immunomodulatory effects of LXRs.
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http://dx.doi.org/10.1074/jbc.M605237200DOI Listing
October 2006

Liver X receptor-dependent repression of matrix metalloproteinase-9 expression in macrophages.

J Biol Chem 2003 Mar 16;278(12):10443-9. Epub 2003 Jan 16.

Howard Hughes Medical Institute, University of California, Los Angeles 90095, USA.

Matrix metalloproteinases (MMPs) are zinc endopeptidases that degrade extracellular matrix (ECM) components during normal and pathogenic tissue remodeling. Inappropriate expression of these enzymes contributes to the development of vascular pathology, including atherosclerosis. MMP-9 is expressed in its active form in atherosclerotic lesions and is believed to play an important role in vascular remodeling, smooth muscle cell migration, and plaque instability. We demonstrate here that the liver X receptors (LXRs) LXRalpha and LXRbeta inhibit basal and cytokine-inducible expression of MMP-9. Treatment of murine peritoneal macrophages with the synthetic LXR agonists GW3965 or T1317 reduces MMP-9 mRNA expression and blunts its induction by pro-inflammatory stimuli including lipopolysaccharide, interleukin-1beta, and tumor necrosis factor alpha. In contrast, macrophage expression of MMP-12 and MMP-13 is not altered by LXR ligands. We further show that the ability of LXR ligands to regulate MMP-9 expression is strictly receptor-dependent and is not observed in macrophages obtained from LXRalphabeta null mice. Analysis of the 5'-flanking region of the MMP-9 gene indicates that LXR/RXR heterodimers do not bind directly to the MMP-9 promoter. Rather, activation of LXRs represses MMP-9 expression, at least in part through antagonism of the NFkappaB signaling pathway. These observations identify the regulation of macrophage MMP-9 expression as a mechanism whereby activation of LXRs may impact macrophage inflammatory responses.
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http://dx.doi.org/10.1074/jbc.M213071200DOI Listing
March 2003