A recent study by the American scientists investigated how dietary changes influence liver homeostasis. Results showed that switching from ad libitum feeding to intermittent fasting promotes rapid proliferation of hepatocytes in mice.
Nutrient availability fluctuates in most natural populations, forcing organisms to undergo periods of fasting and re-feeding. In contrast to other organs, the liver maintains a constant ratio with body weight to preserve homeostasis—this is called the hepatostat. When injured, the liver restores this ratio through the renewal of hepatocytes, resulting in the liver’s ability to maintain numerous metabolic functions.
Hepatocyte turnover along the liver lobule has been well characterized during ad libitum feeding, when animals have constant access to food. In these studies, hepatocytes showed a detectable rate of turnover and division, but the rate of proliferation compared to other tissues was low.
Pericentral hepatocytes, present near the central vein, receive different growth factor signals compared to the midlobular and periportal hepatocytes that occupy the rest of the liver lobule. Pericentral hepatocytes receive paracrine Wnt signals from the endothelial cells of the central vein, which is necessary to establish and maintain the zonation and function of pericentral hepatocyte in the liver. Wnt signaling is one of the central mechanisms regulating morphogenesis during embryogenesis, repair and self-renewal of some tissues in mammals.
The study provides evidence of the influence of diet on adult hepatocyte proliferation and challenges the widely held view that liver tissue is mostly quiescent unless chemically or mechanically injured.
About the study
The aim of this study was to determine the impact of intermittent fasting on hepatocyte turnover by comparing the presence of the proliferation marker Ki67 in the hepatocytes at 1- and 3-week of intermittent fasting treatment to ad libitum treatment.
The expression of Ki67+ hepatocytes throughout the liver lobule was evauated by using a pericentral hepatocyte marker (glutamine synthetase) and a periportal hepatocyte marker (E-cadherin).
The results showed that switching from ad libitum feeding to intermittent fasting promotes rapid proliferation of hepatocytes. Total number of Ki67+ hepatocytes increased by 2-fold at 1 week of intermittent fasting treatment compared to ad libitum treatment. The number of pericentral Ki67+ hepatocytes increased by approximately 120% after 1 week of intermittent fasting treatment compared to ad libitum treatment.
However, this increase was no longer seen at 3 weeks of intermittent fasting treatment. At 3 weeks of intermittent fasting treatment, the number of Ki67+ hepatocytes returned to ad libitum level, and Ki67+ hepatocytes were predominately midlobular. These findings suggest that the increase in proliferation was short term.
According to the authors, endocrine fibroblast growth factor (FGF) signaling is essential for mediating an organism’s physiological response to fasting and re-feeding. Upon re-feeding, FGF15, produced by intestinal enterocytes and possibly by other tissues, travels through the bloodstream and binds to its co-receptor on hepatocytes.
The research team demonstrated that expression of FGF15 was rapidly induced upon re-feeding, reaching a maximum level in the intestine within 30 minutes of re-feeding in intermittent fasting animals. In contrast, ad libitum animals did not express detectable FGF15.
The authors also explored why pericentral hepatocytes were preferentially divided in response to intermittent fasting, since FGF15 is theoretically available for all hepatocytes. One hypothesis is that hepatocyte proliferation induced by intermittent fasting requires a second signal, which is concentrated near pericentral hepatocytes.
The results showed that hepatocyte proliferation induced by intermittent fasting is driven by the combined action of the systemic FGF15 and localized Wnt signaling. These findings suggest that the systemic FGF15 and paracrine Wnt pathways work together to push hepatocytes through the cell cycle.
As summary, in order to proliferate in response to intermittent fasting, hepatocytes integrate nutrient sensing responses, mediated by FGF15, with knowledge of cellular position, mediated by local, pericentral Wnt signals. Pericentral hepatocyte proliferation ensures the replacement of the lost cellular mass by an increase in the total number of cells. The authors actually propose a working model in which paracrine Wnt and endocrine FGF pathways work together to push hepatocytes through different phases of the cell cycle.
The research team also investigated whether the hepatostat was disrupted during intermittent fasting. For early periods of intermittent fasting (2–6 days), the liver-to-body weight ratio decreased significantly during fasting, but increased during re-feeding compared to ad libitum-treated animals. However, after 3 weeks of intermittent fasting, this ratio stabilized and was not significantly different between fasting, re-feeding or ad libitum animals. This means that hepatocyte proliferation during periods of fasting and re-feeding re-establishes a constant liver-to-body mass ratio, maintaining the hepatostat.
This study showed that intermittent fasting modified the homeostatic regenerative program and highlighted the role of FGF/Wnt signaling interactions in modulating regeneration associated with fasting. It appears that the liver is perfectly tuned to changes in nutritional status and deploys robust homeostatic mechanisms to ensure a constant liver-to-body weight ratio during fasting and re-feeding. The authors concluded that their results demonstrated that there is perhaps greater proliferation capacity than previously appreciated in tissues that are currently thought to have a slow turnover rate.
This article is published in the scientific journal eLife. Sarkar A. et al. Intermittent fasting induces rapid hepatocyte proliferation to restore the hepatostat in the mouse liver. eLife 2023; 12:e82311. (Open Access) https://doi.org/10.7554/eLife.82311