Hepatobiliary Pathophysiology of Liver Regeneration

Washington University, Saint Louis MO

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Abstract

The long-term objective of this research program is the elucidation of the molecular mechanisms of hepatic regeneration in pediatric liver diseases. The specific goals of this project are to determine the functional role of adipsin expression and complement pathway activation in the regulation of hepatic regeneration. Recently, we reported that the early regenerating liver transiently activates a program of adipocytic gene expression and hepatocellular fat accumulation, and that disruption of this adipogenic response results in impaired regeneration. These observations suggest that this adipogenic program is regulated during and essential for normal liver regeneration. One of the genes identified as induced as part of this response in regenerating liver is adipsin. Adipsin, also known as complement factor D, is a unique serine protease whose only known substrate target is C3b-bound complement factor B, which it cleaves during complement alternative pathway activation. Adipsin and factor B are not required for complement classical pathway activation. Complement factor 3 (C3) is the principal target of activation of both pathways. Together, these observations suggest that the complement alternative pathway may be an important regulator of the hepatic regenerative response. In support of this, our preliminary data show that liver regeneration is abnormal in both CS-deficient- and adipsin-deficient-mice. Surprisingly, our data indicate that the regenerative response is more severely disrupted in adipsin-deficient animals than in C3-null mice. Based on these data, we hypothesize that hepatic adipogenic changes and complement alternative pathway activation are essential for initiation of normal liver regeneration and furthermore that adipsin may have complement-independent activity during liver regeneration. In order to test this hypothesis, we propose the following aims: (1) To test whether complement cascade activation is essential for normal liver regeneration and determine the mechanistic basis of this requirement;(2) To test whether adipsin expression and complement alternative pathway activation are required for normal liver regeneration;and, (3) To test whether adipsin exhibits complement cascade-independent activity during liver regeneration. The public health implication of these studies relates to their likelihood of increasing our understanding of the mechanisms that regulate hepatic regeneration in response to liver injury, and, ultimately, leading to the development of better diagnostic and therapeutic tools for managing human liver diseases.