Universität zu Köln

Yu, Xiaojie ORCID: 0000-0001-9777-8553, Elfimova, Natalia, Mueller, Marion, Bachurski, Daniel, Koitzsch, Ulrike, Drebber, Uta, Mahabir, Esther, Hansen, Hinrich P., Friedman, Scott L., Klein, Sabine, Dienes, Hans Peter, Hoesel, Marianna, Buettner, Reinhard, Trebicka, Jonel, Kondylis, Vangelis ORCID: 0000-0002-6970-8731, Mannaerts, Inge ORCID: 0000-0002-2235-2555 and Odenthal, Margarete ORCID: 0000-0002-2424-0960 (2022). Autophagy-Related Activation of Hepatic Stellate Cells Reduces Cellular miR-29a by Promoting Its Vesicular Secretion. Cell. Mol. Gastroenterol. Hepatol., 13 (6). S. 1701 - 1717. SAN DIEGO: ELSEVIER INC. ISSN 2352-345X

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Abstract

BACKGROUND & AIMS: Liver fibrosis arises from long-term chronic liver injury, accompanied by an accelerated wound healing response with interstitial accumulation of extracellular matrix (ECM). Activated hepatic stellate cells (HSC) are the main source for ECM production. MicroRNA29a (miR-29a) is a crucial antifibrotic miRNA that is repressed during fibrosis, resulting in up-regulation of collagen synthesis. METHODS: Intracellular and extracellular miRNA levels of primary and immortalized myofibroblastic HSC in response to profibrogenic stimulation by transforming growth factor /5 (TGF/5) or platelet-derived growth factor-BB (PDGF-BB) or upon inhibition of vesicular transport and autophagy processes were determined by quantitative polymerase chain reaction. Autophagy flux was studied by electron microscopy, flow cytometry, immunoblotting, and immunocytochemistry. Hepatic and serum miR-29a levels were quantified by using both liver tissue and serum samples from a cohort of chronic hepatitis C virus patients and a murine CCl4 induced liver fibrosis model. RESULTS: In our study, we show that TGF# and PDGF-BB resulted in decrease of intracellular miR-29a and a pronounced increase of vesicular miR-29a release into the supernatant. Strikingly, miR-29a vesicular release was accompanied by enhanced autophagic activity and up-regulation of the autophagy marker protein LC3. Moreover, autophagy inhibition strongly prevented miR-29a secretion and repressed its targets' expression such as Col1A1. Consistently, hepatic miR-29a loss and increased LC3 expression in myofibroblastic HSC were associated with increased serum miR-29a levels in CCl4-treated murine liver fibrosis and specimens of hepatitis C virus patients with chronic liver disease. CONCLUSIONS: We provide evidence that activation-associated autophagy in HSC induces release of miR-29a, whereas inhibition of autophagy represses fibrogenic gene expression in part through attenuated miR-29a secretion

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Yu, Xiaojie UNSPECIFIED orcid.org/0000-0001-9777-8553 UNSPECIFIED Elfimova, Natalia UNSPECIFIED UNSPECIFIED UNSPECIFIED Mueller, Marion UNSPECIFIED UNSPECIFIED UNSPECIFIED Bachurski, Daniel UNSPECIFIED UNSPECIFIED UNSPECIFIED Koitzsch, Ulrike UNSPECIFIED UNSPECIFIED UNSPECIFIED Drebber, Uta UNSPECIFIED UNSPECIFIED UNSPECIFIED Mahabir, Esther UNSPECIFIED UNSPECIFIED UNSPECIFIED Hansen, Hinrich P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Friedman, Scott L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Klein, Sabine UNSPECIFIED UNSPECIFIED UNSPECIFIED Dienes, Hans Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoesel, Marianna UNSPECIFIED UNSPECIFIED UNSPECIFIED Buettner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Trebicka, Jonel UNSPECIFIED UNSPECIFIED UNSPECIFIED Kondylis, Vangelis UNSPECIFIED orcid.org/0000-0002-6970-8731 UNSPECIFIED Mannaerts, Inge UNSPECIFIED orcid.org/0000-0002-2235-2555 UNSPECIFIED Odenthal, Margarete UNSPECIFIED orcid.org/0000-0002-2424-0960 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-685692
DOI:	10.1016/j.jcmgh.2022.02.013
Journal or Publication Title:	Cell. Mol. Gastroenterol. Hepatol.
Volume:	13
Number:	6
Page Range:	S. 1701 - 1717
Date:	2022
Publisher:	ELSEVIER INC
Place of Publication:	SAN DIEGO
ISSN:	2352-345X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GROWTH-FACTOR; TGF-BETA; TRANSFORMING GROWTH-FACTOR-BETA-1; EXTRACELLULAR VESICLES; LIVER; EXPRESSION; REGULATOR; PATHWAYS; FIBROSIS; REVEALS Multiple languages Gastroenterology & Hepatology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68569