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Povero D, Panera N, Eguchi A, et al. Lipid-induced hepatocyte-derived extracellular vesicles regulate hepatic stellate cell via microRNAs targeting PPAR-γ. Cell Mol Gastroenterol Hepatol. 2015;1(6):646-663.e4doi: 10.1016/j.jcmgh.2015.07.007.
Povero, D., Panera, N., Eguchi, A., Johnson, C. D., Papouchado, B. G., de Araujo Horcel, L., Pinatel, E. M., Alisi, A., Nobili, V., & Feldstein, A. E. (2015). Lipid-induced hepatocyte-derived extracellular vesicles regulate hepatic stellate cell via microRNAs targeting PPAR-γ. Cellular and molecular gastroenterology and hepatology, 1(6), 646-663.e4. https://doi.org/10.1016/j.jcmgh.2015.07.007
Povero, Davide, et al. "Lipid-induced hepatocyte-derived extracellular vesicles regulate hepatic stellate cell via microRNAs targeting PPAR-γ." Cellular and molecular gastroenterology and hepatology vol. 1,6 (2015): 646-663.e4. doi: https://doi.org/10.1016/j.jcmgh.2015.07.007
Povero D, Panera N, Eguchi A, Johnson CD, Papouchado BG, de Araujo Horcel L, Pinatel EM, Alisi A, Nobili V, Feldstein AE. Lipid-induced hepatocyte-derived extracellular vesicles regulate hepatic stellate cell via microRNAs targeting PPAR-γ. Cell Mol Gastroenterol Hepatol. 2015 Nov 01;1(6):646-663.e4. doi: 10.1016/j.jcmgh.2015.07.007. PMID: 26783552; PMCID: PMC4714359.
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Cell Mol Gastroenterol Hepatol. 2015 Nov 01;1(6):646-663.e4. doi: 10.1016/j.jcmgh.2015.07.007.

Lipid-induced hepatocyte-derived extracellular vesicles regulate hepatic stellate cell via microRNAs targeting PPAR-γ.

Cellular and molecular gastroenterology and hepatology

Davide Povero, Nadia Panera, Akiko Eguchi, Casey D Johnson, Bettina G Papouchado, Lucas de Araujo Horcel, Eva M Pinatel, Anna Alisi, Valerio Nobili, Ariel E Feldstein

Affiliations

  1. Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.
  2. Hepato-Metabolic Disease Unit and Liver Research Unit, Bambino-Gesu' Children's Hospital, IRCCS, 00165, Roma, Italy.
  3. Department of Pathology, VA San Diego Healthcare System, San Diego, CA 92103, USA.
  4. Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.; Centro Universitário Lusiada, Santos, 11050-071, Brazil.
  5. Institute of Biomedical Technologies, National Research Council, 20090, Segrate Milano, Italy.

PMID: 26783552 PMCID: PMC4714359 DOI: 10.1016/j.jcmgh.2015.07.007

Abstract

BACKGROUND&AIMS: Hepatic stellate cells (HSCs) play a key role in liver fibrosis in various chronic liver disorders including nonalcoholic fatty liver disease (NAFLD). The development of liver fibrosis requires a phenotypic switch from quiescent to activated HSCs. The triggers for HSCs activation in NAFLD remain poorly understood. We investigated the role and molecular mechanism of extracellular vesicles (EVs) released by hepatocytes during lipotoxicity in modulation of HSC phenotype.

METHODS: EVs were isolated from fat-laden hepatocytes by differential centrifugation and incubated with HSCs. EV internalization and HSCs activation, migration and proliferation were assessed. Loss- and gain-of-functions studies were performed to explore the potential role of PPAR-γ-targeting miRNAs carried by EVs into HSC.

RESULTS: Hepatocyte-derived EVs released during lipotoxicity are efficiently internalized by HSCs resulting in their activation, as shown by marked up-regulation of pro-fibrogenic genes (Collagen-I, α-SMA and TIMP-2), proliferation, chemotaxis and wound healing responses. These changes were associated with miRNAs shuttled by EVs and suppression of PPAR-γ expression in HSC. Hepatocyte-derived EVs miRNA content included various miRNAs that are known inhibitors of PPAR-γ expression with miR-128-3p being the most effectively transferred. Furthermore loss- and gain-of-function studies identified miR-128-3p as a central modulator of the effects of EVs on PPAR-γ inhibition and HSC activation.

CONCLUSION: Our findings demonstrate a link between fat-laden hepatocyte-derived EVs and liver fibrosis and have potential implications for the development of novel anti-fibrotic targets for NAFLD and other fibrotic diseases.

Keywords: Extracellular Vesicles; Hepatic Stellate Cell; Lipotoxicity; Liver Fibrosis; miRNAs

Conflict of interest statement

None

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