The precision with which the liver:body mass ratio is regulated in health and restored by regeneration after injury has been recognized for thousands of years, as indicated by the legend of Prometheus from ancient Greek mythology,23
and extensive experimental analyses have been conducted to identify the responsible mechanisms. Nevertheless, the specific signals that regulate liver:body mass with such remarkable fidelity have not been fully elucidated, and further studies are needed before the potential benefits that such understanding might offer towards clinical management of patients with liver diseases are fully realized. Several lines of evidence suggest that important signals involved in regulating liver mass may come from the small intestine. For example, some studies have shown that hepatic regeneration is impaired after extensive SBR,4,5
and we have previously reported that liver mass is decreased after proximal SBR.3
Based on these observations, the studies reported here were conducted in order to further characterize the changes that occur in liver:body mass after partial small bowel resection, including determination as to whether such changes involve both physical and functional liver mass and identification of candidate mechanistic mediators of this effect. The results showed that following proximal SBR, liver:body mass is significantly decreased with comparably decreased total hepatic tissue protein and transaminase activity, indicating that SBR results in loss of functional, metabolically active liver tissue. A similar decrease in liver:body mass was noted after distal SBR, indicating that the mechanisms responsible for decreased liver mass in this model do not depend on region-specific functions of the small intestine. For example, these mechanisms are not likely to depend on bile-acid-dependent regulation of FXR activity, which has been shown to regulate liver mass 8
but depends primarily on active reabsorption of bile acids in the distal small intestine.24
Our data also showed that by 7 days after SBR liver:body mass, total hepatic transaminase activity, and total hepatic protein had recovered. This timing of recovery correlates with, and may result from, signals derived from the intestinal adaptive response, whose onset is detectable as early as 24 h after SBR and which plateaus 7 days after such surgery.25,26
Our studies also identified a molecular marker of autophagic activation (LC3-II) increased in liver tissue recovered from mice subjected to bowel resection, raising the possibility that autophagy may contribute to loss of liver tissue in this model. Autophagy is an ancient, evolutionarily conserved mechanisms by which eukaryotic cells degrade and remove redundant, senescent, or defective proteins and organelles.16,17
This pathway has been shown to regulate cell size,18
which is intriguing in light of our observation that partial bowel resection also results in decreased hepatocellular cross-sectional area. Autophagy is increasingly being studied because of emerging links between its dysregulation and human diseases, including liver diseases. For example α1-antitrypsin deficiency associated liver disease has been associated with increased hepatocellular autophagy.27
In addition, autophagy has recently been implicated as a candidate mediator of acute liver cell damage in patients with anorexia nervosa.28
Given the established link between nutritional deprivation and autophagic activation,17
these data highlight the possibility that, despite comparable post-operative dietary intake in SBR versus sham-operated mice, the bowel resected animals may suffer from some degree of relative nutritional deprivation related to reduced small bowel absorptive capacity. Alternatively, the small bowel may be the source of a non-nutritive signal that regulates autophagy. Based on the data presented here, future studies should investigate the impact of pharmacological or genetic interventions that disrupt autophagy on regulation of liver:body mass after SBR.
Finally, our studies also showed increased hepatic expression of the pro-apoptotic protein Bax in proportion to the anti-apoptotic protein Bcl-2 after partial bowel resection. However, our inability to detect evidence of hepatic activation of downstream markers of apoptotic activation, such as caspase 3 and 9 activation, PARP cleavage, or TUNEL staining raised the possibility that hepatic apoptotic progression may be specifically inhibited in this setting. To address this we investigated hepatic mRNA expression of several IAP family members. None of these was identified as significantly up-regulated after SBR. It is intriguing to note that hepatocellular apoptosis was not identified in anorexia nervosa patients with acute liver injury.28
Nevertheless, the functional role that apoptosis plays in the changes that occur in functional liver mass after small bowel resection remains to be further defined, and future analyses investigating the effects of genetic or pharmacological disruption of apoptotic pathways on changes in liver mass after SBR may provide additional insight.