Role of membrane associated molecules in liver fibrosis

The aim of the study was to evaluate the role of membrane associated proteins in tissue formation and remodeling, in normal embryogenesis and in liver disease. Molecules associated with cellular membranes provide a fundamental basis for cellular interactions during development, homeostasis and disease. Similar basic mechanisms play a crucial role in liver disease such as in tissue modeling during embryogenesis.

In the first study we investigated the expression of the cell adhesion molecule R-cadherin during formation of muscle and parenchymatous organs in the developing mouse embryo. R-cadherin was expressed during myogenesis in a pattern suggesting that it plays a role in myoblast cell-cell interactions. R-cadherin was also expressed by epithelia. In kidney, the expression pattern was associated with mesenchymal-epithelial interactions. R-cadherin exclusively rescued formation of epithelia and muscle in teratomas derived from E-cadherin null embryonic stem cells. From the results of this study we concluded that R-cadherin plays a role in formation of striated muscle and possibly also of epithelia.

In the second study, we evaluated the role of neural cell adhesion molecule (N-CAM) in biliary type fibrosis and liver fibrosis due to parenchymatous disease. N-CAM knock-out mice had attenuated liver fibrosis after bile duct ligation but not after carbon tetrachloride injections. Furthermore, hepatic stellate cells isolated from N-CAM knock-outs had impaired activation. These results suggest a role of N-CAM in biliary type liver fibrosis.

In the third study we studied the distribution of EBP50 in patients with biliary liver disease. EBP50 is a scaffolding protein involved in stabilization of transport proteins at the plasma membrane. EBP50 was normally expressed in hepatocytes and native bile ducts of patients with cystic fibrosis carrying the CFTR mutation deltaF508, primary biliary cirrhosis and primary sclerosing cholangitis. However, EBP50 was delocalized to the basolateral membranes, cytoplasm and nucleus in proliferating cells of the ductular reactions. This finding, together with suppressed proliferation of cultured cholangiocytes when EBP50 is down-regulated, suggests that it has a role the in proliferation of biliary epithelial cells in biliary liver disease.

Liver fibrosis due to long-term treatment with methotrexate is related to continuous low-grade hepatocellular damage. In the fourth study we evaluated the impact of the risk factors diabetes, over-weight, alcohol and viral hepatitis on development of liver fibrosis in methotrexate treated psoriasis patients. The results showed that patients with over-weight and/or diabetes had significantly higher risk of developing liver fibrosis and cirrhosis, at a lower accumulative dose methotrexate.

List of scientific papers

I. Rosenberg P, Esni F, Sjödin A, Larue L, Carlsson L, Gullberg D, Takeichi M, Kemler R, Semb H (1997). A potential role of R-cadherin in striated muscle formation. Dev Biol. 187(1): 55-70
https://pubmed.ncbi.nlm.nih.gov/9224674

II. Rosenberg P, Söderberg C, Sjöström M, Kinnman N, Stål P, Hultcrantz R (2008). Attenuated liver fibrosis after bile duct ligation and defect hepatic stellate cell activation in N-CAM knockout mice. [Manuscript]

III. Fouassier L, Rosenberg P, Martine M, Saubaméa B, Kinnman N,| Chignard N, Strandvik B, Barbu V, Hultcrantz R, Housset C (2008). EBP50, a CFTR-binding protein, with cellular redistribution in biliary diseases, controls cholangiocyte proliferation. [Manuscript]

IV. Rosenberg P, Urwitz H, Johannesson A, Ros AM, Lindholm J, Kinnman N, Hultcrantz R (2007). Psoriasis patients with diabetes type 2 are at high risk of developing liver fibrosis during methotrexate treatment. J Hepatol. 46(6): 1111-8. Epub 2007 Feb 15
https://pubmed.ncbi.nlm.nih.gov/17399848