Universität zu Köln

Sommer, Judith, Dorn, Christoph ORCID: 0000-0002-2560-9598, Gaebele, Erwin, Bataille, Frauke, Freese, Kim, Seitz, Tatjana, Thasler, Wolfgang E., Buettner, Reinhard, Weiskirchen, Ralf ORCID: 0000-0003-3888-0931, Bosserhoff, Anja ORCID: 0000-0001-8147-394X and Hellerbrand, Claus (2020). Four-And-A-Half LIM-Domain Protein 2 (FHL2) Deficiency Aggravates Cholestatic Liver Injury. Cells, 9 (1). BASEL: MDPI. ISSN 2073-4409

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Abstract

Cholestasis occurs in different clinical circumstances and leads to severe hepatic disorders. The four-and-a-half LIM-domain protein 2 (FHL2) is a scaffolding protein that modulates multiple signal transduction pathways in a tissue- and cell context-specific manner. In this study, we aimed to gain insight into the function of FHL2 in cholestatic liver injury. FHL2 expression was significantly increased in the bile duct ligation (BDL) model in mice. In Fhl2-deficient (Fhl2-ko) mice, BDL caused a more severe portal and parenchymal inflammation, extended portal fibrosis, higher serum transaminase levels, and higher pro-inflammatory and pro-fibrogenic gene expression compared to wild type (wt) mice. FHL2 depletion in HepG2 cells with siRNA resulted in a higher expression of the bile acid transporter Na+-taurocholate cotransporting polypeptide (NTCP) gene. Furthermore, FHL2-depleted HepG2 cells showed higher expression of markers for oxidative stress, lower B-cell lymphoma 2 (Bcl2) expression, and higher Bcl2-associated X protein (BAX) expression after stimulation with deoxycholic acid (DCA). In hepatic stellate cells (HSCs), FHL2 depletion caused an increased expression of TGF-beta and several pro-fibrogenic matrix metalloproteinases. In summary, our study shows that deficiency in FHL2 aggravates cholestatic liver injury and suggests FHL2-mediated effects on bile acid metabolisms and HSCs as potential mechanisms for pronounced hepatocellular injury and fibrosis.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Sommer, Judith UNSPECIFIED UNSPECIFIED UNSPECIFIED Dorn, Christoph UNSPECIFIED orcid.org/0000-0002-2560-9598 UNSPECIFIED Gaebele, Erwin UNSPECIFIED UNSPECIFIED UNSPECIFIED Bataille, Frauke UNSPECIFIED UNSPECIFIED UNSPECIFIED Freese, Kim UNSPECIFIED UNSPECIFIED UNSPECIFIED Seitz, Tatjana UNSPECIFIED UNSPECIFIED UNSPECIFIED Thasler, Wolfgang E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Buettner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Weiskirchen, Ralf UNSPECIFIED orcid.org/0000-0003-3888-0931 UNSPECIFIED Bosserhoff, Anja UNSPECIFIED orcid.org/0000-0001-8147-394X UNSPECIFIED Hellerbrand, Claus UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-351372
DOI:	10.3390/cells9010248
Journal or Publication Title:	Cells
Volume:	9
Number:	1
Date:	2020
Publisher:	MDPI
Place of Publication:	BASEL
ISSN:	2073-4409
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language EXPRESSION; FIBROSIS; CELLS; INFLAMMATION; MCP-1 Multiple languages Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/35137