Elucidating the metabolic regulation of liver regeneration

Abstract

The regenerative capability of liver is well known, and the mechanisms that regulate liver regeneration are extensively studied. Such analyses have defined general principles that govern the hepatic regenerative response and implicated specific extracellular and intracellular signals as regulated during and essential for normal liver regeneration. Nevertheless, the most proximal events that stimulate liver regeneration and the distal signals that terminate this process remain incompletely understood. Recent data suggest that the metabolic response to hepatic insufficiency might be the proximal signal that initiates regenerative hepatocellular proliferation. This review provides an overview of the data in support of a metabolic model of liver regeneration and reflects on the clinical implications and areas for further study suggested by these findings.

Figure 1

The metabolic and hepatocellular proliferative responses to partial hepatectomy. Blood glucose, indexed body mass, hepatic triglyceride content, liver/body weight ratio, plasma free fatty acids, percentage hepatocellular bromodeoxyuridine (BrdU) incorporation, and hepatocellular mitotic frequency per high-powered field (HPF; A) and liver histological features (H&E) and BrdU immunohistochemistry (B) at serial times after partial hepatectomy (black circles) or sham (white circles) surgery in mice. Scale bar = 100 μm.

Figure 2

Evidence for the functional importance of the metabolic response to hepatic insufficiency during liver regeneration. Summary of the experimental manipulations of metabolism reported to influence liver regeneration that are discussed in the text.

Figure 3

A metabolic model of liver regeneration. Summary of the candidate molecular mechanisms that link altered metabolism and regulation of liver regeneration that are discussed in the text.