**5.2 Lipophagy**

In addition to the actions of lipolysis, lipophagy plays a role in lipid mobilization and degradation in hepatocytes (**Figure 3**). Lipophagy could act as the downstream of lipolysis, since large LDs could produce small LDs by re-esterification *via* ATGL that can subsequently be targeted by lipophagy [64]. Depending on the manner of LDs transportation into lysosomes and vacuoles, lipophagy could be divided into macroand microautophagy [52]. Macrolipophagy involves the autophagosome-mediated LDs sequestration and their subsequent delivery to lysosomes/vacuole for degradation by lysosomal acid lipase, while microlipophagy is the process through which LDs and lysosomes take place direct physical interaction and transferation of lipids [65]. Inhibition of lipophagy could lead to TG and LDs accumulation *in vitro* and *in vivo*, a decrease in TG breakdown and a colocalization between TG components and TG or LDs proteins [52, 66]. Dysregulation of lipophagy may induce hepatic lipid accumulation and therefore lead to NAFLD.

Increasing evidence supports the ATGL-mediated interplay between lipolysis and lipophagy for different size of LDs [66]. Lysosomal inhibition has been shown to lead to the accumulation of small LDs within autophagosomes, which demonstrated that macrolipophagy primarily targets small LDs. Study identifies that ATGL participates in neutral lipolysis to decrease the size of large LDs and create small newly LDs, accessible for sequestration of macrolipophagy, *via* FAs re-esterification [67]. ATGL may also activate sirtuin 1 (SIRT1) to promote LDs degradation by macrolipophagy [68]. Besides, ER stress inhibits macrolipophagy by downregulating the fusion between the autophagosome and the lysosome, which could lead to accumulation of ubiquitinated proteins and LDs that in turn increase ER stress and reactive oxygen species (ROS) production. HFD-induced mice liver may lead to the altered lipid composition of autophagosomes and/or lysosomes, which in turn affects their fusion and impaired lipophagy [69]. In addition, excess nutrient supply may alter the upstream kinase pathways of lipophagy and impair its function. The MAP3K5/ASK1 (mitogenactivated protein kinase 5), a regulator of the MAPK signaling cascades, negatively correlates with hepatic lipids accumulation and NASH scores, and positively correlates with TG level, suggesting its macroautophagy-related protective role [70], on the other hand MAP3K5 inhibition is reported to reduce hepatic lipid accumulation and inflammation [71]. The effect of MAP3K5 on NAFLD may need to be further investigated.

In some cases, lysosomes can directly engulf one relatively large LD, supporting the existence of microlipophagy in hepatocytes. Compared with macroautophagy, microlipophagy may be a more efficient pathway for small LDs degradation without
