For Publishers
DiscoveryMetadataPeer reviewHostingPublishing
For Researchers
JoinPublishReviewCollect
Register
Blog
About
Search
Advanced search
My ScienceOpen
Search
For Publishers
For Researchers
Blog
About
7
views
31
references
 Top references
cited by
11
    
0 reviews
 Review
0
comments
 Comment
0
recommends
+1 Recommend
0 collections
    0
    shares
      124
      similar
       All similar
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      22‐S‐Hydroxycholesterol protects against ethanol‐induced liver injury by blocking the auto/paracrine activation of MCP‐1 mediated by LXRα

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Chronic ethanol consumption causes hepatic steatosis and inflammation, which are associated with liver hypoxia. Monocyte chemoattractant protein‐1 ( MCP‐1) is a hypoxia response factor that determines recruitment and activation of monocytes to the site of tissue injury. The level of MCP‐1 is elevated in the serum and liver of patients with alcoholic liver disease ( ALD); however, the molecular details regarding the regulation of MCP‐1 expression are not yet understood completely. Here, we show the role of liver X receptor α ( LXR α) in the regulation of MCP‐1 expression during the development of ethanol‐induced fatty liver injury, using an antagonist, 22‐ S‐hydroxycholesterol (22‐ S‐ HC). First, administration of 22‐ S‐ HC attenuated the signs of liver injury with decreased levels of MCP‐1 and its receptor CCR2 in ethanol‐fed mice. Second, hypoxic conditions or treatment with the LXR α agonist GW3965 significantly induced the expression of MCP‐1, which was completely blocked by treatment with 22‐ S‐ HC or infection by shLXR α lentivirus in the primary hepatocytes. Third, over‐expression of LXR α or GW3965 treatment increased MCP‐1 promoter activity by increasing the binding of hypoxia‐inducible factor‐1 α to the hypoxia response elements, together with LXR α. Finally, treatment with recombinant MCP‐1 increased the level of expression of LXR α and LXR α‐dependent lipid droplet accumulation in both hepatocytes and Kupffer cells. These data show that LXR α and its ligand‐induced up‐regulation of MCP‐1 and MCP‐1‐induced LXR α‐dependent lipogenesis play a key role in the autocrine and paracrine activation of MCP‐1 in the pathogenesis of alcoholic fatty liver disease, and that this activation may provide a promising new target for ALD therapy.Copyright © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

          Related collections

          Most cited references31

          • Record: found
          • Abstract: found
          • Article: not found

          Hypoxia-inducible factor 1alpha is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signaling motif.

          Andrew Tee, Stephen Land (2007)
          Tumors that form as a result of heightened mammalian target of rapamycin (mTOR) signaling are highly vascularized. This process of angiogenesis is regulated through hypoxia-inducible factor (HIF)-mediated transcription of angiogenic factors. It is recognized that inhibition of mTOR with rapamycin can diminish the process of angiogenesis. Our work shows that activation of mTOR by Ras homologue enriched in brain (Rheb) overexpression potently enhances the activity of HIF1alpha and vascular endothelial growth factor (VEGF)-A secretion during hypoxia, which is reversed with rapamycin. Mutants of Rheb, which do not bind guanine nucleotide (D60K, D60V, N119I, and D122N) and are unable to activate mTOR, inhibit the activity of HIF when overexpressed. We show that regulatory associated protein of mTOR (Raptor) interacts with HIF1alpha and requires an mTOR signaling (TOS) motif located in the N terminus of HIF1alpha. Furthermore, a mutant of HIF1alpha lacking this TOS motif dominantly impaired HIF activity during hypoxia and was unable to bind to the co-activator CBP/p300. Rapamycin treatments do not affect the stability of HIF1alpha and modulate HIF activity via a Von Hippel-Lindau (VHL)-independent mechanism. We demonstrate that the high levels of HIF activity in cells devoid of TSC2 can be reversed by treatments with rapamycin or the readdition of TSC2. Our work explains why human cancers with aberrant mTOR signaling are prone to angiogenesis and suggests that inhibition of mTOR with rapamycin might be a suitable therapeutic strategy.
          Article 0 comments Cited 161 times – based on 0 reviews     Review now
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Ethanol induces fatty acid synthesis pathways by activation of sterol regulatory element-binding protein (SREBP).

            M Deeg, Min You, D Crabb … (2002)
            Alcoholic fatty liver is the earliest and most common response of the liver to alcohol and may be a precursor of more severe forms of liver injury. The mechanism by which ethanol causes fatty liver and liver injury is complex. We found that in both rat H4IIEC3 and McA-RH7777 hepatoma cell lines, ethanol induced transcription of a sterol regulatory element-binding protein (SREBP)-regulated promoter via increased levels of mature SREBP-1 protein. This effect of ethanol was blocked by addition of sterols. This effect is likely mediated by acetaldehyde, because the effect was only seen in cell lines expressing alcohol dehydrogenase, and inhibition of ethanol oxidation by 4-methylpyrazole blocked the effect in the hepatoma cells. Furthermore, the aldehyde dehydrogenase inhibitor cyanamide enhanced the effect of ethanol in the hepatoma cells. Consistent with these in vitro findings, feeding mice a low fat diet with ethanol for 4 weeks resulted in a significant increase in steady-state levels of the mature (active) form of SREBP-1. Activation of SREBP-1 by ethanol feeding was associated with increased expression of hepatic lipogenic genes as well as the accumulation of triglyceride in the livers. These finding suggest that metabolism of ethanol increased hepatic lipogenesis by activating SREBP-1 and that this effect of ethanol may contribute to the development of alcoholic fatty liver.
            Article 0 comments Cited 134 times – based on 0 reviews     Review now
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              An essential role for monocyte chemoattractant protein-1 in alcoholic liver injury: regulation of proinflammatory cytokines and hepatic steatosis in mice.

              Pranoti Mandrekar, Gyongyi Szabo, Aditya Ambade … (2011)
              The importance of chemokines in alcoholic liver injury has been implicated. The role of the chemokine, monocyte chemoattractant protein-1 (MCP-1), elevated in patients with alcoholic liver disease is not yet understood. Here, we evaluated the pathophysiological significance of MCP-1 and its receptor, chemokine (C-C motif) receptor 2 (CCR2), in alcoholic liver injury. The Leiber-DeCarli diet containing alcohol or isocaloric control diets were fed to wild-type (WT) and MCP-1-deficient knockout (KO) mice for 6 weeks. In vivo and in vitro assays were performed to study the role of MCP-1 in alcoholic liver injury. MCP-1 was increased in Kupffer cells (KCs) as well as hepatocytes of alcohol-fed mice. Alcohol feeding increased serum alanine aminotransferase in WT and CCR2KO, but not MCP-1KO, mice. Alcohol-induced liver steatosis and triglyceride were attenuated in alcohol-fed MCP-1KO, but high in CCR2KO mice, compared to WT, whereas serum endotoxin was high in alcohol-fed WT and MCP-1KO mice. Expression of liver proinflammatory cytokines tumor necrosis factor alpha, interleukin (IL)-1β, IL-6, KC/IL-8, intercellular adhesion molecule 1, and cluster of differentiation 68 was induced in alcohol-fed WT, but inhibited in MCP-1KO, mice independent of nuclear factor kappa light-chain enhancer of activated B cell activation in KCs. Oxidative stress, but not cytochrome P450 2E1, was prevented in chronic alcohol-fed MCP-1KO mice, compared to WT. Increased expression of peroxisome proliferator-activated receptor (PPAR)α and PPARγ was accompanied by nuclear translocation, DNA binding, and induction of fatty acid metabolism genes acyl coenzyme A oxidase and carnitine palmitoyltransferase 1A in livers of alcohol-fed MCP-1KO mice, compared to WT controls. In vitro assays uncovered an inhibitory effect of recombinant MCP-1 on PPARα messenger RNA and peroxisome proliferator response element binding in hepatocytes independent of CCR2. Deficiency of MCP-1 protects mice against alcoholic liver injury, independent of CCR2, by inhibition of proinflammatory cytokines and induction of genes related to fatty acid oxidation, linking chemokines to hepatic lipid metabolism. Copyright © 2011 American Association for the Study of Liver Diseases.
              Article 0 comments Cited 114 times – based on 0 reviews     Review now
                Bookmark
                All references

                Author and article information

                Journal
                Journal ID (nlm-ta): J Pathol
                Journal ID (iso-abbrev): J. Pathol
                Journal ID (doi): 10.1002/(ISSN)1096-9896
                Journal ID (publisher-id): PATH
                Title: The Journal of Pathology
                Publisher: John Wiley & Sons, Ltd (Chichester, UK )
                ISSN (Print): 0022-3417
                ISSN (Electronic): 1096-9896
                Publication date (Electronic): 05 January 2015
                Publication date (Print): April 2015
                Volume: 235
                Issue: 5 ( doiID: 10.1002/path.2015.235.issue-5 )
                Pages: 710-720
                Affiliations
                [ 1 ] College of Pharmacy Seoul National University Korea
                [ 2 ] Research Institute of Pharmaceutical Sciences Seoul National University Korea
                [ 3 ] Bio‐MAX Institute Seoul National University Korea
                Author notes
                [*] [* ]Correspondence to:MO Lee, College of Pharmacy, Seoul National University, San 56‐1 Sillim‐dong, Kwanak‐gu, Seoul 151‐742, Korea. E‐mail: molee@ 123456snu.ac.kr
                Article
                Publisher ID: PATH4494
                DOI: 10.1002/path.4494
                PMC ID: 6084351
                PubMed ID: 25557254
                SO-VID: 93b4bb0f-0b59-4b7f-9088-e9ed2634dc54
                Copyright © Copyright © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                Date received : 07 July 2014
                Date revision received : 05 November 2014
                Date accepted : 29 November 2014
                Page count
                Pages: 11
                Categories
                Subject: Original Paper
                Subject: Original Papers
                Custom metadata
                source-schema-version-number 2.0
                component-id path4494
                cover-date April 2015
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.4 mode:remove_FC converted:09.08.2018

                ScienceOpen disciplines: Pathology
                Keywords: lxrα,mcp‐1,hif‐1,alcoholic liver disease
                Data availability:
                ScienceOpen disciplines: Pathology
                Keywords: lxrα, mcp‐1, hif‐1, alcoholic liver disease

                Comments

                Comment on this article

                scite_

                Similar content124

                See all similar

                Cited by11

                See all cited by

                Most referenced authors433

                See all reference authors