Autophagy: a multifaceted partner in liver fibrosis

Abstract

Liver fibrosis is a common wound healing response to chronic liver injury of all causes, and its end-stage cirrhosis is responsible for high morbidity and mortality worldwide. Fibrosis results from prolonged parenchymal cell apoptosis and necrosis associated with an inflammatory reaction that leads to recruitment of immune cells, activation and accumulation of fibrogenic cells, and extracellular matrix accumulation. The fibrogenic process is driven by hepatic myofibroblasts, that mainly derive from hepatic stellate cells undergoing a transdifferentiation from a quiescent, lipid-rich into a fibrogenic myofibroblastic phenotype, in response to paracrine/autocrine signals produced by neighbouring inflammatory and parenchymal cells. Autophagy is an important regulator of liver homeostasis under physiological and pathological conditions. This review focuses on recent findings showing that autophagy is a novel, but complex, regulatory pathway in liver fibrosis, with profibrogenic effects relying on its direct contribution to the process of hepatic stellate cell activation, but with antifibrogenic properties via indirect hepatoprotective and anti-inflammatory properties. Therefore, cell-specific delivery of drugs that exploit autophagic pathways is a prerequisite to further consider autophagy as a potential target for antifibrotic therapy.

Figure 1

Impact of autophagy on the cellular effectors of liver fibrogenesis. (a) Autophagy drives hepatic stellate cell activation from a quiescent, lipid-rich to a myofibroblastic, fibrogenic phenotype. In response to chronic liver injury, quiescent hepatic stellate cells lose their retinyl ester-containing lipid droplets and acquire myofibroblastic features, associated with fibrogenic properties. Autophagy in hepatic stellate cells is stimulated by oxidative and endoplasmic reticulum stress and may serve to provide free fatty acids from retinyl esters, thereby supplying the energy required for initiating and perpetuating the fibrogenic phenotype. (b) Autophagy as a protective anti-inflammatory process with antifibrogenic properties. Hepatic macrophage autophagy stimulates an anti-inflammatory pathway, that reuses the production of IL1 alpha and IL1 beta, resulting in inhibition of liver fibrogenesis. In addition, inhibition of Th17 polarisation by IL1 alpha and beta may also contribute to the antifibrogenic effects of macrophagic autophagy. (c) Hepatoprotective properties of autophagy may contribute to inhibition of fibrogenesis. Autophagy is generally considered as a survival pathway for hepatocytes, therefore limiting oxidative stress profibrogenic pathways for hepatic stellate cells such as ER stress and mitochondrial damage.

Figure 2

Autophagy in the liver: a pathway with divergent cell-specific effects? Autophagy enhances fibrogenic properties in hepatic stellate cells. In contrast, anti-inflammatory effects in macrophages and hepatoprotective effects in hepatocytes limit the development of liver fibrosis.