Antifibrotic effects of hypocalcemic vitamin D analogs in murine and human hepatic stellate cells and in the CCl4 mouse model

Reiter, Florian P.; Ye, Liangtao; Boesch, Florian; Wimmer, Ralf; Artmann, Renate; Ziesch, Andreas; Kanitz, Veronika; Mayr, Doris; Steib, Christian J.; Trauner, Michael; Regel, Ivonne; Gerbes, Alexander L.; Mayerle, Julia; Hohenester, Simon; Toni, Enrico N. de und Denk, Gerald (2019): Antifibrotic effects of hypocalcemic vitamin D analogs in murine and human hepatic stellate cells and in the CCl4 mouse model. In: Laboratory Investigation, Bd. 99, Nr. 12: S. 1906-1917

Abstract

Liver cirrhosis is a life-threatening consequence of liver fibrosis. The aim of this study was to investigate the antifibrotic potential of clinically available vitamin D analogs compared to that of calcitriol in vitro and in vivo. Murine hepatic stellate cells, Kupffer cells, and human LX-2 cells were treated with vitamin D analogs, and the profibrotic behavior of these cells was studied. In vivo liver fibrosis was induced using CCl4 until measurable fibrosis was established. Animals were then treated with calcitriol and paricalcitol. Vitamin D and its analogs showed antifibrotic effects in vitro. Treatment with active vitamin D (calcitriol, CAL) and its analogs reduced the protein expression of alpha-smooth muscle actin (alpha-SMA) in mHSC. In human LX-2 cells alfacalcidol reduced transforming growth factor-beta (TGF-beta) induced platelet-derived growth factor receptor-beta protein expression and contractility while paricalcitol (PCT), in its equipotent dose to CAL, reduced TGF-beta induced alpha-SMA protein expression, and ACTA2 and TGF-beta mRNA expression. No effects of a treatment with vitamin D and its analogs were observed in Kupffer cells. In vivo, PCT-treated mice had significantly lower calcium levels than CAL-treated mice. CAL and PCT reduced the hepatic infiltration of CD11b-positive cells and alanine transaminase levels, while PCT but not CAL significantly inhibited fibrosis progression, with a favorable side effect profile in the CCl4 model. We conclude that hypocalcemic vitamin D analogs should be considered in future studies investigating vitamin D for the treatment of liver fibrosis.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0023-6837
• Sprache: Englisch