Liver regeneration: molecular mechanisms of growth control

TLDR

Molecular signals controlling liver regeneration are rapidly defined, with new liver‑specific growth factors identified and gene expression patterns established, and growth responses may be modulated by mitogenic factors and comitogenic substances such as norepinephrine and TGFβ. The study examines how TGFβ contributes to stopping DNA synthesis during liver regeneration, outlining evidence for its paradoxical role. Key mitogenic growth factors—including EGF, TGFα, aFGF, HPTA/HGF, and Hepatopoietin B—have been identified, with HPTA/HGF possessing a large, structurally homologous sequence, and the work also highlights TGFβ’s paradoxical role in halting DNA synthesis. Published in FASEB Journal, 1990, 4:176‑187.

Abstract

The molecular signals controlling liver regeneration are becoming rapidly defined. Control of growth in regenerating liver has advanced from elusive serum factors and nutrient effects to identification of entirely new growth factors with apparent liver specificity as well as establishment of meaningful gene expression patterns for growth factors already known. Based on studies with hepatocyte cultures and gene expression in regenerating liver, the substances EGF, TGFα, HBGF-1 (aFGF), and two new substances (HPTA/HGF and Hepatopoietin B) have been defined as complete mitogens for hepatocytes and implicated in control of liver growth. The amino acid sequence of HPTA/HGF recently became clear and revealed interesting structural homologies in a molecule that might become the largest known growth factor. The plasticity of growth responses seen in liver may be controlled by these factors as well as by comitogenic substances such as norepinephrine which, although nonmitogenic per se, can initiate growth in hepatocytes exposed to the above mitogenic growth factors or mitogenic inhibitors such as TGFβ. The role of the latter in cessation of DNA synthesis in liver regeneration will be discussed, presenting the positive and negative evidence that constitutes the TGFβ paradox of liver regeneration.—Michalopoulos, G. K. Liver regeneration: molecular mechanisms of growth control. FASEB J. 4: 176-187; 1990.