Four-And-A-Half LIM-Domain Protein 2 (FHL2) Deficiency Aggravates Cholestatic Liver Injury

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-β 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.

Bone morphogenetic protein 13 in hepatic stellate cells and hepatic fibrosis

“…16 BMP13 expression was already detectable in freshly isolated cells, but the mRNA and protein expression further increased during the course of in vitro activation of HSC (Figure 1A,B). Fitting to the activation of HSC in response to liver injury, we found two-to threefold increased BMP13 expression in two experimental models of liver fibrosis in mice, namely, surgically induced cholestasis by bile duct ligation (BDL) 13 (Figure 1C) and dietary-induced nonalcoholic steatohepatitis (NASH) 17 (Figure 1D). In silico analysis of 110 human liver tissue samples applying the GEPIA database 18 showed a significant correlation between the expression of BMP13 and α-SMA, a marker for activated HSC 19 (Figure 1E).…”

How (Epi)Genetic Regulation of the LIM-Domain Protein FHL2 Impacts Multifactorial Disease

“…In the liver FHL2 levels are relatively low, but upon overexpression in this organ in mice the balance of hepatocyte proliferation and apoptosis is disturbed, leading to inflammation and cirrhosis. Furthermore, in FHL2-KO mice the liver shows increased fibrosis and an exacerbated response in a cholestatic injury model [34][35][36]. FHL2 has been detected in kidney podocytes where it interacts with and activates the Wnt/β-catenin signaling pathway [37].…”

Special Issue on “Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis”

“…Similarly, novel important functions were shown for the four-and-a-half LIM-domain protein 2 (FHL2) supposed to act as a scaffolding protein. Sommer and colleagues now provide novel insights in the role of FHL2 in cholestatic liver injury with a special focus on hepatocellular damage and fibrosis [25]. The authors found that Fhl2-deficient mice develop significantly more hepatic damage and inflammation when subjected to bile-duct ligation than normal control mice.…”

“…These articles cover a wide range of aspects showing that this fascinating field has made conceptual advances that hopefully will lead to novel treatment options in the near future. 25 countries. These contributions discuss aspects of basic, clinical and translational research in the field of liver fibrosis.…”