28 August: Scientists have taken a step forward in understanding the mechanisms of liver regeneration, with new data highlighting the potential regenerative properties of the enzyme monoacylglycerol lipase (MAGL) presented at The Digital International Liver Congress™ 2020. Experiments using mice and hepatic cell culture showed how MAGL activity promotes liver regeneration, and how hepatocytes and specific immune cells are involved in this process.
Liver transplantation remains the only treatment for end-stage liver disease or acute liver failure but obtaining donor organs is extremely challenging. However, the ability of liver tissue to regenerate and self-repair has made it a key focus of research into regenerative medicine, in an attempt to find alternatives to transplantation. MAGL is a proinflammatory enzyme that reprograms lipid metabolism by converting monoacylglycerols into free fatty acids, specifically 2-arachidonoylglycerol - an endocannabinoid receptor ligand - into arachidonic acid. Reprogramming lipid metabolism in different liver cell types has become an increasing area of focus in targeting fibrosis progression/regression. Previously, both genetic (MAGL-/-) and pharmacological (using MJN110 inhibitor) invalidation of MAGL has been shown to reduce inflammation and slow fibrosis progression in mice.
Now, scientists from the same team have used these techniques to investigate whether inhibition of MAGL could affect liver regeneration. They found that MAGL-invalidated mice who had their liver damaged (either by 2/3 partial hepatectomy or acute intraperitoneal injection of carbon tetrachloride) had impaired liver regeneration compared with wild-type counterparts. This was reflected by fewer BrdU+ hepatocytes and reduced Cyclin A expression. MAGL deficiency was associated with a lower production of inflammatory mediators (PGE2) and reduced mRNA expression of TGF-?, IL-17, and HGF after liver injury. Mice with MAGL specifically inactivated in hepatocytes or myeloid cells showed similar impairment in liver regeneration. In the latter, impaired liver regeneration was associated with a decrease in hepatic TNF production. However, there was no effect on hepatocyte proliferation in mice with MAGL inactivated within lymphocytes. In vitro studies confirmed a decreased proliferation index in primary hepatocytes exposed to MJN110 or isolated from MAGL knockout mice compared with wild-type mouse tissue.
"Inhibition of MAGL is associated with compromised liver regeneration, that results both from a direct effect on hepatocytes and an indirect effect on macrophages", said Dr Manon Allaire from the UMR 1149 Centre de Recherche sur l'Inflammation, France. "Thus, while being profibrogenic, MAGL displays proregenerative capacities in the liver".
"In an ideal world, therapies for end-stage liver diseases would target fibrosis and promote liver regeneration simultaneously", said Professor Saskia van Mil from the University Medical Center in Utrecht, The Netherlands, and an EASL Governing Board Member. "The data presented here show that targeting lipid metabolism, more specifically MAGL, during end-stage liver disease may in fact have opposite effects on fibrosis and regeneration. This is an intriguing finding with implications for MAGL's therapeutic value for chronic liver disease and potentially other therapeutic lipid metabolism targets."
About The International Liver Congress™
This annual congress is EASL's flagship event, attracting scientific and medical experts from around the world to learn about the latest in liver research and exchange clinical experience. Attending specialists present, share, debate and conclude on the latest science and research in hepatology, working to enhance the treatment and management of liver disease in clinical practice. This year, the congress is being held entirely digitally due to the global health situation. The Digital International Liver Congress™ 2020 will take place from 27-29 August 2020. For more information on attendance and registration, please visit https://ilc-congress.eu/.
About The European Association for the Study of the Liver (EASL)
Since its foundation in 1966, this not-for-profit organization has grown to over 4,500 members from all over the world, including many of the leading hepatologists in Europe and beyond. EASL is the leading liver association in Europe, having evolved into a major European association with international influence, and with an impressive track record in promoting research in liver disease, supporting wider education, and promoting changes in European liver policy.
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Session title: General session II and award ceremony
Date and time of session: Friday 28 August 2020, 13.15-13.30
Presenter: Manon Allaire
Abstract: Monoacylglycerol lipase reprograms lipid metabolism in macrophages and hepatocytes to promote liver regeneration
Manon Allaire has no relevant disclosures.
1. Nicolas CT, et al. Liver regenerative medicine: from hepatocyte transplantation to bioartificial livers and bioengineered grafts. Stem Cells. 2017;35(1):42-50.
2. Habib A, et al. Inhibition of monoacylglycerol lipase, an anti-inflammatory and antifibrogenic strategy in the liver. Gut. 2019;68:522-32.
Journal of Hepatology