The Functional Role of Furin in the Liver During Homeostasis and Pathological Conditions: A Journey of Challenges and Pitfalls in Transgene Technology

The biological role of hepatic Furin was investigated using conditional knock-out approaches in homeostatic and challenged conditions, including liver regeneration and HCC. On the one hand, the genetic inactivation of Furin in the liver under homeostatic conditions using AlfpCre Recombinase technology led to the characterization of an artifact related to the AlfpCre transgene explaining the phenotypes of post-natal growth retardation and liver steatosis. This type of artifact in Cre recombinase technology involves the use of the hGH minigene as a source of introns and a polyadenylation signal. In AlfpCre mice, this led to its expression in the hypothalamus and pituitary gland, causing GH deficiency and subsequently post-natal growth retardation and liver steatosis. On the other hand, liver regeneration and HCC challenged the liver in the setting of hepatic Furin deficiency. This led to a normal liver regenerative response, but an accelerated ASVB-induced tumor formation with significantly larger tumors due to an increased proliferation index in the early stage. The identification of FURIN substrates remains a subject of further research and may give more insights into why hepatic Furin deficiency led to a differential phenotype with regards to proliferation between liver regeneration and HCC.status: publishe