Lipophagy and liver disease: New perspectives to better understanding and therapy

Intracellular lipid droplets (LDs) are remarkably dynamic and complex organelles that enact regulated storage and release of lipids to fulfil their fundamental roles in energy metabolism, membrane synthesis and provision of lipid-derived signaling molecules. The recent finding that LDs can be selectively degraded by the lysosomal pathway of autophagy through a process termed lipophagy has opened up a new understanding of how lipid metabolism regulates cellular physiology and pathophysiology. Many new functions for autophagic lipid metabolism have now been defined in various diseases including liver disease. Lipophagy was originally described in hepatocytes, where it is critical for maintaining cellular energy homeostasis in obesity and metabolic syndrome. In vitro and in vivo studies have demonstrated the selective uptake of LDs by autophagosomes, and inhibition of autophagy has been shown to reduce the β-oxidation of free fatty acids due to the increased accumulation of lipids and LDs. The identification of lipophagy as a new process dedicated to cellular lipid removal has mapped autophagy as an emerging player in cellular lipid metabolism. Pharmacological or genetic modulation of lipophagy might point to possible therapeutic strategies for combating a broad range of liver diseases. This review summarizes recent work focusing on lipophagy and liver disease as well as highlighting challenges and future directions of research. On the other hand, it also offers a glimpse into different strategies that have been used in experimental models to counteract excessive pathological lipophagy in the prevention and treatment of liver disease.