The effect of LOXL2 enzyme inhibition on liver fibrosis

Townsend, Sarah (2020). The effect of LOXL2 enzyme inhibition on liver fibrosis. University of Birmingham. M.D.

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Abstract

Fibrosis is the final common pathway of all chronic liver injury, and its pathological endpoint, cirrhosis, carries a growing and substantial health burden, accounting for over 2.5% of deaths worldwide. Lysyl oxidase-like protein 2 (LOXL2) is one of a family of five (LOX, LOXL1-4) amine oxidases expressed by fibrogenic cells. This enzyme oxidises lysine residues in collagens and elastin leading to covalent crosslinking and stabilisation of structural components within the extracellular matrix, conferring the tensile strength of collagen and elastic fibers. In the liver, LOXL2 is believed to contribute significantly to fibrogenesis, and inhibition of its enzymatic activity may have therapeutic benefit.

The aim of this study was to investigate the effect of LOXL2 enzyme inhibition in vivo using murine models of liver fibrosis and on fibroblast activity in vitro.

Preliminary data was gained by examining tissue from mice and rats receiving developmental compounds developed to inhibit LOXL2 in thioacetamide and carbon tetrachloride induced fibrosis. A selected pre-clinical compound was then tested in our own model of TAA induced fibrosis and fibrosis resolution, the Mdr2-/- model of biliary fibrosis, and during in vitro studies.

The results show that inhibition of LOXL2 with PXS5303 and PXS5338K did not significantly reduce fibrosis in murine models of liver injury and that PXS5338K did not alter fibroblast activity at concentrations expected to inhibit LOXL2. The compound PXS5338K demonstrated some efficacy in reducing CCl4-induced liver fibrosis in rats.

In conclusion, enzyme inhibition of LOXL2 has not demonstrated significant efficacy in reducing liver fibrosis during in vitro or in vivo testing in mice.

Type of Work:

Thesis (Doctorates > M.D.)

Award Type:

Doctorates > M.D.

Supervisor(s):