ArticleHepatology (Baltimore, Md.)2015
Liver X receptors balance lipid stores in hepatic stellate cells through Rab18, a retinoid responsive lipid droplet protein.
Article in Hepatology (Baltimore, Md.), 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 44 citations in OpenAlex.
- Hepatic stellate cell-specific miR-214 expression alleviates liver fibrosis without boosting steatosis and inflammation.Journal of translational medicine · 2025Article
- Formation and Investigation of Cell-Derived Nanovesicles as Potential Therapeutics against Chronic Liver Disease.Advanced healthcare materials · 2023Article
- The Small GTPase Rab14 Regulates the Trafficking of Ceramide from Endoplasmic Reticulum to Golgi Apparatus and Facilitates Classical Swine Fever Virus Assembly.Journal of virology · 2023Article
- Retinoids in the Pathogenesis and Treatment of Liver Diseases.Nutrients · 2022Review
- Redox Control of Integrin-Mediated Hepatic Inflammation in Systemic Autoimmunity.Antioxidants & redox signaling · 2022Review
- Liver fibrosis and retinal features in an older Mediterranean population: Results from the Salus in Apulia study.Frontiers in neuroscience · 2022Article
- A retinoic acid receptor β2 agonist attenuates transcriptome and metabolome changes underlying nonalcohol-associated fatty liver disease.The Journal of biological chemistry · 2021Article
- Extra- and Intra-Cellular Mechanisms of Hepatic Stellate Cell Activation.Biomedicines · 2021Review
- Friend or Foe: Lipid Droplets as Organelles for Protein and Lipid Storage in Cellular Stress Response, Aging and Disease.Molecules (Basel, Switzerland) · 2020Review
- Lipophagy: Molecular Mechanisms and Implications in Metabolic Disorders.Molecules and cells · 2020Review
- SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis.Nature communications · 2020Article
- Review
- Liver X Receptors Regulate Cholesterol Metabolism and Immunity in Hepatic Nonparenchymal Cells.International journal of molecular sciences · 2019Review
- Hepatocyte and stellate cell deletion of liver fatty acid binding protein reveals distinct roles in fibrogenic injury.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2019Article
- In vitro inhibition of hepatic stellate cell activation by the autophagy-related lipid droplet protein ATG2A.Scientific reports · 2018Article
- Lipometabolism and Glycometabolism in Liver Diseases.BioMed research international · 2018Review
- Relevance of Rab Proteins for the Life Cycle of Hepatitis C Virus.Frontiers in cell and developmental biology · 2018Review
- The lipid droplet: A conserved cellular organelle.Protein & cell · 2017Review
- Hepatic stellate cells as key target in liver fibrosis.Advanced drug delivery reviews · 2017Review
- A RasGAP, DAB2IP, regulates lipid droplet homeostasis by serving as GAP toward RAB40C.Oncotarget · 2017Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
unlabelledLiver X receptors (LXRs) are determinants of hepatic stellate cell (HSC) activation and liver fibrosis. Freshly isolated HSCs from Lxrαβ(-/-) 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 Lxrαβ(-/-) 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. Lxrαβ(-/-) HSCs have increased cholesterol and retinyl esters. The retinoid increase drives intrinsic retinoic acid receptor signaling, and activation occurs more rapidly in Lxrαβ(-/-) 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 Lxrαβ(-/-) 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.
conclusionRetinoid and cholesterol metabolism are linked in stellate cells by the LD-associated protein Rab18. Retinoid overload helps explain the profibrotic phenotype of Lxrαβ(-/-) 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.