The Role of Autophagy for the Regeneration of the Aging Liver

Abstract

Age is one of the key risk factors to develop malignant diseases leading to a high incidence of hepatic tumors in the elderly population. The only curative treatment for hepatic tumors is surgical removal, which initiates liver regeneration. However, liver regeneration is impaired with aging, leading to an increased surgical risk for the elderly patient. Due to the increased risk, those patients are potentially excluded from curative surgery. Aging impairs autophagy via lipofuscin accumulation and inhibition of autophagosome formation. Autophagy is a recycling mechanism for eukaryotic cells to maintain homeostasis. Its principal function is to degrade endogenous bio-macromolecules for recycling cellular substances. A number of recent studies have shown that the reduced regenerative capacity of the aged remnant liver can be restored by promoting autophagy. Autophagy can be activated via multiple mTOR-dependent and mTOR-independent pathways. However, inducing autophagy through the mTOR-dependent pathway alone severely impairs liver regeneration. In contrast, recent observations suggest that inducing autophagy via mTOR-independent pathways might be promising in promoting liver regeneration. Conclusion: Activation of autophagy via an mTOR-independent autophagy inducer is a potential therapy for promoting liver regeneration, especially in the elderly patients at risk.

Keywords: AMPK; TFEB; ULK1; hepatectomy; hepatocyte; mTOR; proliferation.

Figure 1

Overview of liver regeneration stages. After partial hepatectomy, every stage is governed by specific transcription factors and cytokines. Under their tight regulation, hepatocytes undergo the process from initiation to termination of proliferation.

Figure 2

The dynamic process of autophagy. Macroautophagy mainly includes the following steps: (A) Phagophore formation. Activation of the Class III PtdIns3K complex produces PI3P, which facilitates the nucleation of phagophores and regulates the degradation of autophagy cargo [106]. (B) Phagophore elongation and capture of degradation targets. The function of the transmembrane protein Atg9 is to deliver the membrane from donor organelles to the expanding phagophore [107]. The LC3-II and Atg12–Atg5–Atg16L complex promotes phagophore elongation [106]. (C) Autophagosome formation. p62 interacts with the autophagy cargo and delivers it to the autophagosome. (D) Fusion of the autophagosome with lysosome; (E) Degradation of the cargo.

Figure 3

Signaling pathways and modulators involved in the regulation of macroautophagy. mTOR is a key regulator for both autophagy and cell proliferation. Autophagy can be activated in the mTOR-dependent and the mTOR-independent signaling pathways. Dark blue square: autophagy inducer; Dark red square: autophagy inhibitor.

Figure 4

The relationship between autophagy, liver regeneration and aging. (A) mTOR-independent autophagy inducers can promote liver regeneration, while (B) mTOR-dependent autophagy inducers inhibit liver regeneration.