Liver X receptors balance lipid stores in hepatic stellate cells through Rab18, a retinoid responsive lipid droplet protein
Open accessAbstract
Liver X receptors (LXRs) are determinants of hepatic stellate cell (HSC) activation and liver fibrosis. Freshly isolated HSCs from Lxr αβ−/− mice have increased lipid droplet (LD) size, but the functional consequences of this are unknown. Our aim was to determine whether LXRs link cholesterol to retinoid storage in HSCs and how this impacts activation. Primary HSCs from Lxr αβ−/− and wild‐type mice were profiled by gene array during in vitro activation. Lipid content was quantified by high‐performance liquid chromatography and mass spectroscopy. Primary HSCs were treated with nuclear receptor ligands, transfected with small interfering RNA and plasmid constructs, and analyzed by immunocytochemistry. Lxr αβ−/− HSCs have increased cholesterol and retinyl esters. The retinoid increase drives intrinsic retinoic acid receptor signaling, and activation occurs more rapidly in Lxr αβ−/− HSCs. We identify Rab18 as a novel retinoic acid‐responsive, LD‐associated protein that helps mediate stellate cell activation. Rab18 mRNA, protein, and membrane insertion increase during activation. Both Rab18 guanosine triphosphatase activity and isoprenylation are required for stellate cell LD loss and induction of activation markers. These phenomena are accelerated in Lxr αβ−/− HSCs, where there is greater retinoic acid flux. Conversely, Rab18 knockdown retards LD loss in culture and blocks activation, just like the functional mutants. Rab18 is also induced with acute liver injury in vivo. Conclusion: Retinoid and cholesterol metabolism are linked in stellate cells by the LD‐associated protein Rab18. Retinoid overload helps explain the profibrotic phenotype of Lxr αβ−/− mice, and we establish a pivotal role for Rab18 GTPase activity and membrane insertion in wild‐type stellate cell activation. Interference with Rab18 may have significant therapeutic benefit in ameliorating liver fibrosis. (H epatology 2015;62:615–626
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HSC activation is associated with decreased lipid accumulation.
“HSCs activation was associated with decreased lipid accumulation (Supplementary Fig. 9)45, and thus FXR agonists might inhibit HSCs activation via stabilizing LD.”
From SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis (2020) · cites this paper as [45]
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Cites
Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver
Friedman, S. L. (2008) · Physiological Reviews · doi:10.1152/physrev.00013.2007 · Cited by 2,842 · see citing works
Mederacke, I., Hsu, C. C., Troeger, J. S., Huebener, P., Mu, X., Dapito, D. H., Pradere, J.-P., & Schwabe, R. F. (2013) · Nature Communications · doi:10.1038/ncomms3823 · Cited by 1,443 · see citing works
Reciprocal regulation of inflammation and lipid metabolism by liver X receptors
Joseph, S. B., Castrillo, A., Laffitte, B. A., Mangelsdorf, D. J., & Tontonoz, P. (2003) · Nature Medicine · doi:10.1038/nm820 · Cited by 1,158 · see citing works
Human hepatic stellate cell lines, LX-1 and LX-2: new tools for analysis of hepatic fibrosis
Xu, L., Hui, A. Y., Albanis, E., Arthur, M. J., O’Byrne, S. M., Blaner, W. S., Mukherjee, P., Friedman, S. L., & Eng, F. J. (2004) · Gut · doi:10.1136/gut.2004.042127 · Cited by 1,020 · see citing works
Self-citationHepatic lipocytes: the principal collagen-producing cells of normal rat liver.
Friedman, S. L., Roll, F. J., Boyles, J., & Bissell, D. M. (1985) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.82.24.8681 · Cited by 859 · see citing works
LXR Regulates Cholesterol Uptake Through Idol-Dependent Ubiquitination of the LDL Receptor
Zelcer, N., Hong, C., Boyadjian, R., & Tontonoz, P. (2009) · Science · doi:10.1126/science.1168974 · Cited by 848 · see citing works
Integration of metabolism and inflammation by lipid-activated nuclear receptors
Bensinger, S. J., & Tontonoz, P. (2008) · Nature · doi:10.1038/nature07202 · Cited by 813 · see citing works
Liver X Receptor Signaling Pathways in Cardiovascular Disease
Tontonoz, P., & Mangelsdorf, D. J. (2003) · Molecular Endocrinology · doi:10.1210/me.2003-0061 · Cited by 633 · see citing works
Walther, T. C., & Farese, R. V. (2008) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2008.10.009 · Cited by 478 · see citing works
Hepatic stellate cell lipid droplets: A specialized lipid droplet for retinoid storage
Blaner, W. S., O'Byrne, S. M., Wongsiriroj, N., Kluwe, J., D'Ambrosio, D. M., Jiang, H., Schwabe, R. F., Hillman, E. M. C., Piantedosi, R., & Libien, J. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2008.11.001 · Cited by 444 · see citing works
Self-citationProteome-wide mapping of cholesterol-interacting proteins in mammalian cells
Hulce, J. J., Cognetta, A. B., Niphakis, M. J., Tully, S. E., & Cravatt, B. F. (2013) · Nature Methods · doi:10.1038/nmeth.2368 · Cited by 428 · see citing works
Retinoid absorption and storage is impaired in mice lacking lecithin:retinol acyltransferase (LRAT)
O'Byrne, S. M., Wongsiriroj, N., Libien, J., Vogel, S., Goldberg, I. J., Baehr, W., Palczewski, K., & Blaner, W. S. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m507924200 · Cited by 296 · see citing works
Self-citationVogel, S., Piantedosi, R., Frank, J., Lalazar, A., Rockey, D. C., Friedman, S. L., & Blaner, W. S. (2000) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)32030-7 · Cited by 283 · see citing works
Self-citationGeubel, A. P., de Galocsy, C., Alves, N., Rahier, J., & Dive, C. (1991) · Gastroenterology · doi:10.1016/0016-5085(91)90672-8 · Cited by 232 · see citing works
Nuclear Receptors in Lipid Metabolism: Targeting the Heart of Dyslipidemia
Beaven, S. W., & Tontonoz, P. (2006) · Annual Review of Medicine · doi:10.1146/annurev.med.57.121304.131428 · Cited by 225 · see citing works
Self-citationBielawski, J., Pierce, J. S., Snider, J. M., Rembiesa, B. M., Szulc, Z. M., & Bielawska, A. E. (2009) · Methods in molecular biology · doi:10.1007/978-1-60761-322-0_22 · Cited by 189 · see citing works
Loss-of-Function Mutations in RAB18 Cause Warburg Micro Syndrome
Bem, D., Yoshimura, S., Bastos, R. N., Bond, F. F., Kurian, M. A., Rahman, F., Handley, M. T., Hadzhiev, Y., Masood, I., Straatman-Iwanowska, A. A., et al. (2011) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2011.03.012 · Cited by 172 · see citing works
Suppression of experimental hepatic fibrosis by administration of vitamin A.
Senoo, H., & Wake, K. (1985) · PubMed · Cited by 158 · see citing works
Beaven, S. W., Matveyenko, A. V., Wroblewski, K., Chao, L. C., Wilpitz, D. C., Hsu, T. W., Lentz, J., Drew, B. G., Hevener, A. L., & Tontonoz, P. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.04.021 · Cited by 146 · see citing works
Self-citationOkuno, M. (1997) · Hepatology · doi:10.1053/jhep.1997.v26.pm0009328313 · Cited by 141 · see citing works
Beaven, S. W., Wroblewski, K., Wang, J., Hong, C., Bensinger, S., Tsukamoto, H., & Tontonoz, P. (2011) · Gastroenterology · doi:10.1053/j.gastro.2010.11.053 · Cited by 131 · see citing works
Self-citationKluwe, J., Wongsiriroj, N., Troeger, J. S., Gwak, G., Dapito, D. H., Pradère, J., Jiang, H., Siddiqi, M., Piantedosi, R., O’Byrne, S. M., et al. (2011) · Gut · doi:10.1136/gut.2010.209551 · Cited by 121 · see citing works
Self-citationMoriwaki, H., Blaner, W. S., Piantedosi, R., & Goodman, D. S. (1988) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)38430-3 · Cited by 104 · see citing works
Self-citationDifferential modulation of rat hepatic stellate phenotype by natural and synthetic retinoids
Hellemans, K., Verbuyst, P., Quartier, E., Schuit, F., Rombouts, K., Chandraratna, R. A. S., Schuppan, D., & Geerts, A. (2004) · Hepatology · doi:10.1002/hep.20015 · Cited by 102 · see citing works
Lee, T., Mak, K. M., Rackovsky, O., Lin, Y., Kwong, A. J., Loke, J. C., & Friedman, S. L. (2010) · Journal of Cellular Physiology · doi:10.1002/jcp.22063 · Cited by 102 · see citing works
Vitamin A Intoxication in Adults
STIMSON, W. H. (1961) · New England Journal of Medicine · doi:10.1056/nejm196108242650804 · Cited by 83 · see citing works
Suppression of experimental hepatic fibrosis by administration of vitamin A
妹尾, 春. (1984) · Medical Entomology and Zoology · Cited by 75 · see citing works
Characterization of Rab18, a Lipid Droplet–Associated Small GTPase
Martin, S., & Parton, R. G. (2008) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(07)38008-7 · Cited by 50 · see citing works
Ulven, S. M., Natarajan, V., Holven, K. B., Løvdal, T., Berg, T., & Blomhoff, R. (1998) · European Journal of Cell Biology · doi:10.1016/s0171-9335(98)80078-2 · Cited by 44 · see citing works
Clinical Characteristics of a Large Choroideremia Pedigree Carrying a Novel CHM Mutation
Huang, A. S., Kim, L. A., & Fawzi, A. A. (2012) · Archives of Ophthalmology · doi:10.1001/archophthalmol.2012.1117 · Cited by 38 · see citing works
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Horn, P., & Tacke, F. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.05.003 · Cited by 432 · see citing works
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Zhou, J., Cui, S., He, Q., Guo, Y., Pan, X., Zhang, P., Huang, N., Ge, C., Wang, G., Gonzalez, F. J., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-14138-6 · Cited by 154 · see citing works
- Authors
- O'Mahony, F., Wroblewski, K., O'Byrne, S. M., Jiang, H., Clerkin, K., Benhammou, J., Blaner, W. S., & Beaven, S. W.
- Affiliations
- Division of Digestive Diseases, Department of Medicine,David Geffen School of Medicine at the University of California Los Angeles,Los Angeles, CA,90025,USA
- University of California, Los Angeles (US)
- Department of Medicine,Columbia University,New York, NY,10032,USA
- Columbia University (US)
- Corresponding author
- Beaven, Simon W.
- Venue
- Hepatology
- Published
- 2015-03-23
- Volume
- 62
- Issue
- 2
- Pages
- 615-626
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- PMC
- PMC4458237
- OpenAlex
- W1811253366
- Cited by
- 44
- References
- 30
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2023: 4 · 2022: 3 · 2021: 5 · 2020: 4 · 2019: 4 · 2018: 4 · 2017: 9 · 2016: 4 · 2015: 1
- FWCI
- 2.60
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5k08dk088998-03, 5K08DK088998)
- National Institute on Alcohol Abuse and Alcoholism (R21AA021336)
- National Heart, Lung, and Blood Institute (T35HL007485, T32HL007343, T32HL007854)
- National Institute of Diabetes and Digestive and Kidney Diseases (K08-DK088998, R01DK068437, P30DK041301)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Keywords
- liver X receptor, hepatic stellate cells, stellate cell activation, liver fibrosis, RAB18, lipid droplets, retinoids, retinoic acid receptor signaling, cholesterol metabolism, retinyl esters, isoprenylation, acute liver injury
- MeSH terms
- Liver X Receptors, Animals, Cells, Cultured, Disease Models, Animal, Liver Cirrhosis, Male, Mice, Inbred Strains, Random Allocation, Retinoids, Mass Spectrometry, Signal Transduction, rab GTP-Binding Proteins, Microarray Analysis, Lipid Metabolism, Mice, Hepatic Stellate Cells, Orphan Nuclear Receptors, Real-Time Polymerase Chain Reaction, Lipid Droplets
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