A disintegrin and metalloprotease 10 (ADAM10) is a central regulator of murine liver tissue homeostasis

Abstract

A Disintegrin And Metalloprotease (ADAM) 10 exerts essential roles during organ development and tissue integrity in different organs, mainly through activation of the Notch pathway. However, only little is known about its implication in liver tissue physiology.Here we show that in contrast to its role in other tissues, ADAM10 is dispensable for the Notch2-dependent biliary tree formation. However, we demonstrate that expression of bile acid transporters is dependent on ADAM10. Consequently, mice deficient for Adam10 in hepatocytes, cholangiocytes and liver progenitor cells develop spontaneous hepatocyte necrosis and concomitant liver fibrosis.We furthermore observed a strongly augmented ductular reaction in 15-week old ADAM10Δhep/Δch mice and demonstrate that c-Met dependent liver progenitor cell activation is enhanced. Additionally, liver progenitor cells are primed to hepatocyte differentiation in the absence of ADAM10.These findings show that ADAM10 is a novel central node controlling liver tissue homeostasis.Highlights:Loss of ADAM10 in murine liver results in hepatocyte necrosis and concomitant liver fibrosis.ADAM10 directly regulates expression of bile acid transporters but is dispensable for Notch2-dependent formation of the biliary system.Activation of liver progenitor cells is enhanced through increased c-Met signalling, in the absence of ADAM10.Differentiation of liver progenitor cells to hepatocytes is augmented in the absence of ADAM10.

Metalloproteinases in liver fibrosis: current insights

“…First hints can be seen in study of ADAM10 knockout targeted to hepatocytes, cholangiocytes, and HPC. 78 These animals developed spontaneous fibrosis, which results …”

“…77 However, specific ablation of ADAM10 in hepatocytes did not exhibit alteration in Notch signal, 78 although some percentage of those animals have problems with liver homeostasis manifested by necrosis of hepatocytes and subsequent fibrosis. 78 …”

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

“…The stop cassette was flanked by loxP sites and crossing those global BMAL1 −/− mice with mice that express Cre recombinase under the control of α‐fetoprotein enhancer ( Alfp ‐Cre mice) allowed the removal of the stop cassette specifically in Alfp‐positive hepatic cells . Cre expression is observed selectively in hepatocytes and cholangiocytes in Alfp ‐Cre mice . As a result, crossed mice expressed BMAL1 only in the liver (hepatocytes and cholangiocytes) .…”

“…5 Cre expression is observed selectively in hepatocytes and cholangiocytes in Alfp-Cre mice. 6 As a result, crossed mice expressed BMAL1 only in the liver (hepatocytes and cholangiocytes). 5 Global BMAL1 −/− mice lost circadian rhythms and expressions, but mice with hepatic BMAL1 expression had rhythmic circadian expressions and metabolisms in the liver without BMAL1 expression and circadian rhythms in the brain and other organs.…”

ADAM-Mediated Signalling Pathways in Gastrointestinal Cancer Formation

“…Under these conditions, liver stem and progenitor cells (LPCs) proliferate and differentiate either into hepatocytes or cholangiocytes, the biliary epithelial cells [ 97 ]. ADAM10 was demonstrated to be essential for hepatocellular homeostasis via regulation of bile acid transporters [ 98 ]. Interestingly, in the liver ADAM10 is dispensable for Notch processing and ADAM10-deficient mice display normal formation of the biliary tree [ 98 ] which was linked to Notch2 activity [ 99 ].…”