Autophagy in liver regeneration: Unravelling the endothelial cell's role and therapeutic prospects

Autophagy is a crucial pathway responsible for breaking down and recycling cytoplasmic materials through lysosomes.1 It plays a vital role in maintaining cellular and tissue balance, allowing cells to adapt to various stressors. The process is highly context-specific, and its dysregulation has been linked to several diseases, making it a potential therapeutic target.1 Recent research published in Liver International, by Camprecios et al.2 and Hammoutene et al.,3 independently suggests that endothelial autophagy does not play a role in liver regeneration following experimental partial hepatectomy, using genetically modified mice lacking endothelial autophagy. Liver endothelial cells are essential for orchestrating liver regeneration, as they regulate the balance between hepatocyte proliferation and subsequent vascular growth. After partial hepatectomy, liver endothelial cells promote hepatocyte proliferation through paracrine signalling, proliferate themselves and induce the process of proliferative angiogenesis.4-6 Previous studies have highlighted the significance of autophagy in hepatocytes for successful liver regeneration after partial hepatectomy.7 However, until now, whether autophagy in endothelial cells is crucial for efficient liver regeneration remained unexplored. Camprecios and colleagues investigated this by using Atg7flox/flox;VE-cadherin-Cre+ mice, observing liver regeneration at 0, 2, 4 and 7 days after a 70% partial hepatectomy.2 The researchers found no significant differences in liver weight, function, histology or hepatic proliferation markers between mice deficient in endothelial autophagy and control mice.2 Based on their findings, they concluded that endothelial autophagy is not essential for controlling liver regeneration. In the second study by Hammoutene and colleagues, the authors focused on endothelial autophagy's role in liver regeneration after partial hepatectomy in the context of metabolic-associated liver disease.3 Previous studies already suggested that autophagy promotes progression of metabolic-associated steatotic liver disease.8, 9 The observation that metabolic-associated steatotic liver disease is linked to impaired liver regeneration after hepatectomy prompted the current investigation.10 Atg5lox/lox;VE-cadherin-Cre+ mice and control mice were subjected to three different models of metabolic-associated liver disease: a high-fat diet for 16 weeks, a methionine and choline-deficient diet for 3 weeks and crossing with ApoE−/− hypercholesterolic mice.3 They found that mice lacking endothelial autophagy did not show altered liver regeneration capacity after partial hepatectomy in these metabolic liver disease models.3 Mice fed the high-fat diet and deficient in endothelial autophagy exhibited similar liver weight, transaminase levels, hepatic proliferation and apoptosis markers as control mice at various time points after hepatectomy.3 Similar results were observed in the other two models.3 In summary, recent studies have shed light on the role of autophagy in liver regeneration and its potential therapeutic implications for liver diseases. However, it is important to understand that autophagy can have contrasting effects depending on the cell type, the type of liver injury and the stage of the disease.11 For instance, autophagy deficiency in liver endothelial cells is observed in patients with metabolic-associated steatotic liver disease, and endothelial autophagy deficiency in experimental models for this disease can promote liver inflammation and fibrosis.9 Contrarily, studies on fibrosis showed that mice bearing a specific deletion of autophagy in hepatic stellate cells are resistant to fibrosis and display decreased activation upon chronic carbon tetrachloride administration.12 Selective disruption of autophagy in liver endothelial cells has been shown to impair their ability to handle oxidative stress and aggravate fibrosis in the same experimental model.13 Depending on the specific liver disease, autophagy can be either upregulated or downregulated, leading to impaired liver function and disease progression. Therefore, any approach to target autophagy for modifying the disease course in liver disease will require specific strategies tailored to different cell types. In this regard, the insights provided by Camprecios et al.2 and Hammoutene et al.3 about endothelial autophagy not being required for liver regeneration after partial hepatectomy are crucial for further translational work and the future potential implementation of autophagy-oriented therapies. Although significant progress has been made, there are still areas that require further investigation to fully understand the impact of autophagy on liver health. More research is necessary to identify critical signalling pathways and factors that regulate autophagy in various liver diseases, including the specific autophagic mechanisms involved in hepatocytes and liver endothelial cells at different stages of liver regeneration. Moreover, a deeper understanding is needed of how hepatocytes, liver endothelial cells and other cell types communicate during liver regeneration and how they influence each other's autophagic responses. Autophagy is closely interconnected with various cellular processes, such as apoptosis, inflammation and cellular metabolism. Therefore, additional research is essential to elucidate the crosstalk between autophagy and these processes in the context of liver diseases. Furthermore, the development of safe and effective drugs targeting autophagy for liver diseases remains challenging. More research is required to identify cell-type specific autophagy modulators capable of selectively targeting hepatocytes or liver endothelial cells. By doing so, we may develop therapies that promote liver regeneration while minimising potential adverse effects on other cell types. The authors do not have any disclosures to report. Data sharing is not applicable to this article as no data sets were generated or analysed during the current study.