Luke Eldore

Introduction: Liver fibrosis is a common pathological process seen in numerous liver disease, such as Non-Alcoholic Fatty Liver Disease (NAFLD).¹ NAFLD has nearly a 25% prevalence world-wide, and mild fibrosis is seen in this stage of disease. Fibrosis becomes more prevalent as the liver progresses from NAFLD into Non-Alcoholic Steatohepatitis (NASH), and subsequently progresses to cirrhosis if left untreated.^1-3 There are many factors that contribute to hepatic fibrosis, but the predominant mechanism behind almost all of these causes is chronic liver inflammation.⁴ Lysyl Oxidase like protein (LOXL2) is a key mediator of liver fibrosis and serves as a potential target of anti-fibrosis therapy.⁵ Methods: Mice models were examined to determine the effect of LOXL2 inhibition on fibrosis of the liver. Carbon tetrachloride (CCl4)-induced and gene knockout-induced liver fibrosis models were utilized to mimic the pathogenesis of human liver disease. The effect of various inhibitors of LOXL2 were examined for their potential efficacy. The effect of LOXL2 inhibition on various cell types of the liver were examined as well. Result: Inhibition of LOXL2 by both small molecule or monoclonal antibody leads to reversal of fibrosis.^6-8 This reversal was seen in both CCl4 and gene knockout models indicating LOXL2 as a key mediator in hepatic fibrosis.^6,8 Further, the level of activity of LOXL2 and the level of fibrotic material deposition were demonstrated to have a direct relationship.⁸ In vitro examination of hepatic progenitor cell (HPC) and macrophage activity demonstrated an increase in both HPC and macrophage activity as LOXL2 activity decreased.^6,8 Various inhibitors have been developed for inhibition of LOXL2, with AB0023, a monoclonal antibody, being the most promising.^9,10 Conclusion: Inhibition of LOXL2 will reverse fibrosis of the liver as well as stimulate activity of HPCs and macrophages, both of which will help the liver repair itself and may provide a therapeutic approach to treatment of hepatic fibrosis seen in many liver diseases.

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2. Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, et al. Weight Loss Through Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis. Gastroenterology. 2015;149(2):367-e15. doi:10.1053/j.gastro.2015.04.005
3. Civan JM. Fibrosis of the Liver. merckmanuals.com. https://www.merckmanuals.com/home/liver-and-gallbladder-disorders/fibrosis-and-cirrhosis-of-the-liver/fibrosis-of-the-liver. Published December 2019. Accessed March 5, 2021.
4. Parola M, Pinzani M. Liver fibrosis: Pathophysiology, pathogenetic targets and clinical issues. Mol Aspects Med. 2019;65:37-55. doi:10.1016/j.mam.2018.09.002
5. Barry-Hamilton V, Spangler R, Marshall D, et al. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat Med. 2010;16(9):1009-1017. doi:10.1038/nm.2208
6. Klepfish M, Gross T, Vugman M, et al. LOXL2 Inhibition Paves the Way for Macrophage-Mediated Collagen Degradation in Liver Fibrosis. Front Immunol. 2020;11:480. Published 2020 Mar 31. doi:10.3389/fimmu.2020.00480
7. Dongiovanni P, Meroni M, Baselli GA, et al. Insulin resistance promotes Lysyl Oxidase Like 2 induction and fibrosis accumulation in non-alcoholic fatty liver disease. Clin Sci (Lond). 2017;131(12):1301-1315. Published 2017 Jun 7. doi:10.1042/CS20170175
8. Ikenaga N, Peng ZW, Vaid KA, et al. Selective targeting of lysyl oxidase-like 2 (LOXL2) suppresses hepatic fibrosis progression and accelerates its reversal. Gut. 2017;66(9):1697-1708. doi:10.1136/gutjnl-2016-312473
9. Harrison SA, Abdelmalek MF, Caldwell S, et al. Simtuzumab Is Ineffective for Patients With Bridging Fibrosis or Compensated Cirrhosis Caused by Nonalcoholic Steatohepatitis. Gastroenterology. 2018;155(4):1140-1153. doi:10.1053/j.gastro.2018.07.006
10. Schilter H, Findlay AD, Perryman L, et al. The lysyl oxidase like 2/3 enzymatic inhibitor, PXS-5153A, reduces crosslinks and ameliorates fibrosis. J Cell Mol Med. 2019;23(3):1759-1770. doi:10.1111/jcmm.14074