Impaired liver regeneration in Ldlr−/− mice is associated with an altered hepatic profile of cytokines, growth factors, and lipids

Abstract

Background & Aims It is widely recognized that in the early stages of liver regeneration after partial hepatectomy the hepatocytes accumulate a significant amount of lipids. The functional meaning of this transient steatosis and its effect on hepatocellular proliferation are not well defined. In addition, the basic mechanisms of this lipid accumulation are not well understood although some studies suggest the participation of the Low Density Lipoprotein Receptor (Ldlr). Methods To address these questions we studied the process of liver regeneration in Ldlr null mice and wild-type mice following 75% partial hepatectomy. Results Ldlr deficiency was associated with a significant decrease in serum albumin concentration, during early stages of liver regeneration, and a delayed hepatic regeneration. Remnant livers of Ldlr−/− showed a time-shifted expression of interleukin-6 (IL-6) and a defective activation of tumor necrosis factor-α (TNFα) and hepatocyte growth factor (HGF) expression in early phases of liver regeneration. Unexpectedly, Ldlr−/− showed no significant differences in the content of lipid droplets after partial hepatectomy compared to wild-type mice. However, lipidomic analysis of the regenerating liver from Ldlr−/− revealed a lipid profile compatible with liver quiescence: high content of cholesterol esters and ceramide, and low levels of phosphatidylcholine. Conclusion Ldlr deficiency is associated with significant changes in the hepatic lipidome that affect cytokine-growth factor signaling and impair liver regeneration. These results suggest that the analysis of the hepatic lipidome may help to predict the success of liver regeneration in the clinical environment, specifically in the context of pre-existing liver steatosis.

Akt‐mediated foxo1 inhibition is required for liver regeneration

“…These changes agreed with the temporal distribution of lipid droplets observed in Fig. A and are consistent with the concept that lipid droplets are lipid structures enriched in CEs and TGs . By contrast, the concentration of CE, TGs, and FFAs remained significantly lower in DLKO mice compared with WT mice, without major changes throughout the hepatic regeneration.…”

“…Early stages of liver regeneration are characterized by the formation of hepatocellular lipid droplets and changes in the hepatic lipidome. Several preclinical studies showed that alterations of these features impair hepatocellular proliferation during liver regeneration . To explore whether the hepatic loss of Akt may additionally affect lipid metabolism, we characterized both the hepatic lipid accumulation and the lipidomic profile of livers from WT, DLKO, and TLKO mice before and after PHx.…”

“…Livers (50 mg) were homogenized in 500 μL of phosphate‐buffered saline, and lipids were extracted from 100 μL of the homogenate in the presence of internal standards for each lipid class. The different lipid classes were quantified from the chloroform extracts using shotgun lipidomics based on class separation by tandem mass spectrometry‐specific methods, as described …”

Enhanced Liver Regeneration After Partial Hepatectomy in Sterol Regulatory Element-Binding Protein (SREBP)-1c-Null Mice is Associated with Increased Hepatocellular Cholesterol Availability

“…For histological analysis, the upper right lobe was fixed in 4% neutral paraformaldehyde (PFA) at 4℃ and then cryoprotected overnight in 20% sucrose solution or embedded in Optimal Cutting Temperature medium for future processing. The percentage of liver regeneration was calculated following the formula: Percentage of liver regeneration = weight of non-removed lobes/total body weight of mice × 100% [23].…”

Elucidating Metabolic and Epigenetic Mechanisms that Regulate Liver Regeneration

“…Recently published reports add to this body of literature but do not yet resolve the question. For example, impairment of PH-induced liver regeneration associated with suppression of early hepatic fat accumulation was demonstrated in adipose differentiation related protein (Adrp)-KO- [35], tuberous sclerosis 2 (Tsc2)-haplo-insufficient- [36], and b-glucosylceramide-treated- [37] mice, and LDL-receptor null mice also exhibit delayed regeneration in association with alterations in the hepatic lipidome [38]. The latter finding suggests the interesting possibility that distinct alterations in hepatic lipidomic profiles, in different models in which PHinduced hepatic steatosis is disrupted, might account for the discrepant effects of disrupting hepatic fat accumulation on regeneration noted above and previously.…”