Functional Relationships between Lipid Metabolism and Liver Regeneration

Abstract

The regenerative capacity of the liver is well known, and the mechanisms that regulate this process have been extensively studied using experimental model systems including surgical resection and hepatotoxin exposure. The response to primary mitogens has also been used to investigate the regulation of hepatocellular proliferation. Such analyses have identified many specific cytokines and growth factors, intracellular signaling events, and transcription factors that are regulated during and necessary for normal liver regeneration. Nevertheless, the nature and identities of the most proximal events that initiate hepatic regeneration as well as those distal signals that terminate this process remain unknown. Here, we review the data implicating acute alterations in lipid metabolism as important determinants of experimental liver regeneration and propose a novel metabolic model of regeneration based on these data. We also discuss the association between chronic hepatic steatosis and impaired regeneration in animal models and humans and consider important areas for future research.

Activation of the Transcription Factor GLI1 by WNT Signaling Underlies the Role of SULFATASE 2 as a Regulator of Tissue Regeneration

“…The most important source of lipids that accumulates in the regenerating liver is mainly free fatty acids supplied from adipose tissue. However, de novo hepatic fatty acid synthesis has also been reported (26). According to these observations, our study shows a delay in fat accumulation that is accompanied by a delay in cell proliferation.…”

“…H&E-stained sections show no major abnormalities in the livers of SULF2-KO compared with WT mice at baseline. Microvesicular steatosis, a well-known histopathological feature present during regeneration after PH (22)(23)(24)(25)(26)(27), was seen in both WT and SULF2-KO mouse livers beginning at 12 h after PH. However, 48 h after PH, SULF2-KO mice showed a decrease in microvesicular steatosis compared with WT mice.…”

Identification of an epigenetic signature of early mouse liver regeneration that is disrupted by Zn-HDAC inhibition

“…For example, supplemental glucose affects patterns of histone acetylation in cell culture, [24][25][26] PH-induced hypoglycemia occurs during experimental liver regeneration, and glucose supplementation inhibits regeneration. 7,23,27 In addition, HDAC5 undergoes PH-induced nuclear localization in regenerating liver, 2 and this Zn-HDAC also exhibits hypoglycemia-induced nuclear localization and regulates FOXO target gene expression in other models. 28 Finally, recent studies suggest that specific metabolites modulate isoformspecific HDAC activity in vivo.…”

SAK-HV Triggered a Short-period Lipid-lowering Biotherapy Based on the Energy Model of Liver Proliferation via a Novel Pathway

“…Strey et al demonstrated that IL-6-STAT3 pathway played key roles in regulating liver proliferation mediated by C3a and C5a (14). Liver proliferation is an energy and material-consuming process that causes a dramatic consuming of both TG and cholesterol from serum and liver in a short time (15). Although the detailed lipid regulatory pathway is still unclear, lots of studies have reached a consensus on the lipid metabolic characteristics during this process (15)(16)(17)(18)(19).…”

“…Liver proliferation is an energy and material-consuming process that causes a dramatic consuming of both TG and cholesterol from serum and liver in a short time (15). Although the detailed lipid regulatory pathway is still unclear, lots of studies have reached a consensus on the lipid metabolic characteristics during this process (15)(16)(17)(18)(19). It enhanced fatty acid oxidation in liver for energy production, and upregulated both hepatic cholesterol synthesis and uptake for cell membrane synthesis (15,16).…”