Glycochenodeoxycholate Promotes Liver Fibrosis in Mice with Hepatocellular Cholestasis

Hohenester S, Kanitz V, Kremer A, Paulusma CC, Wimmer R, Kühn H, Denk G, Horst D, Elferink RO, Beuers U (2020)

Publication Type: Journal article

Publication year: 2020

Journal

Cells MDPI

Book Volume: 9

Journal Issue: 2

DOI: 10.3390/cells9020281

Abstract

Hydrophobic bile salts are considered to promote liver fibrosis in cholestasis. However, evidence for this widely accepted hypothesis remains scarce. In established animal models of cholestasis, e.g., by Mdr2 knockout, cholestasis and fibrosis are both secondary to biliary damage. Therefore, to test the specific contribution of accumulating bile salts to liver fibrosis in cholestatic disease, we applied the unique model of inducible hepatocellular cholestasis in cholate-fed Atp8b1(G308V/G308V) mice. Glycochenodeoxycholate (GCDCA) was supplemented to humanize the murine bile salt pool, as confirmed by HPLC. Biomarkers of cholestasis and liver fibrosis were quantified. Hepatic stellate cells (HSC) isolated from wild-type mice were stimulated with bile salts. Proliferation, cell accumulation, and collagen deposition of HSC were determined. In cholestatic Atp8b1(G308V/G308V) mice, increased hepatic expression of alpha SMA and collagen1a mRNA and excess hepatic collagen deposition indicated development of liver fibrosis only upon GCDCA supplementation. In vitro, numbers of myofibroblasts and deposition of collagen were increased after incubation with hydrophobic but not hydrophilic bile salts, and associated with EGFR and MEK1/2 activation. We concluded that chronic hepatocellular cholestasis alone, independently of biliary damage, induces liver fibrosis in mice in presence of the human bile salt GCDCA. Bile salts may have direct pro-fibrotic effects on HSC, putatively involving EGFR and MEK1/2 signaling.

Authors with CRIS profile

Andreas Kremer Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Helen Kühn Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology

Involved external institutions

University of Amsterdam NL Netherlands (NL) Ludwig-Maximilians-Universität (LMU) DE Germany (DE) Charité - Universitätsmedizin Berlin DE Germany (DE)

How to cite

APA:

Hohenester, S., Kanitz, V., Kremer, A., Paulusma, C.C., Wimmer, R., Kühn, H.,... Beuers, U. (2020). Glycochenodeoxycholate Promotes Liver Fibrosis in Mice with Hepatocellular Cholestasis. Cells, 9(2). https://doi.org/10.3390/cells9020281

MLA:

Hohenester, Simon, et al. "Glycochenodeoxycholate Promotes Liver Fibrosis in Mice with Hepatocellular Cholestasis." Cells 9.2 (2020).

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