Lipophagy-derived fatty acids undergo extracellular efflux via lysosomal exocytosis

Cui, Wenqi; Sathyanarayan, Aishwarya; Lopresti, Michael; Aghajan, Mariam; Chen, Chi; Mashek, Douglas G.

doi:10.1080/15548627.2020.1728097

Cited by 70 publications

(54 citation statements)

References 67 publications

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“…As such, lipophagy is important to liberate fatty acids from the TGs stored in the LDs. A recent study reported that lipophagy-derived fatty acids undergo a cycle of efflux followed by reuptake before a subsequent reincorporation into cellular LDs ( 79 ). However, if lipophagy is associated with reduced hepatic lipid content, it is likely that some of the liberated fatty acids will be directed towards FAO.…”

Section: Lipophagy: the Fifth Pathway Involved In Non-alcoholic Fattymentioning

confidence: 99%

The Role of Lipophagy in the Development and Treatment of Non-Alcoholic Fatty Liver Disease

et al. 2021

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Non-alcoholic fatty liver disease (NAFLD) or metabolic (dysfunction) associated liver disease (MAFLD), is, with a global prevalence of 25%, the most common liver disorder worldwide. NAFLD comprises a spectrum of liver disorders ranging from simple steatosis to steatohepatitis, fibrosis, cirrhosis and eventually end-stage liver disease. The cause of NAFLD is multifactorial with genetic susceptibility and an unhealthy lifestyle playing a crucial role in its development. Disrupted hepatic lipid homeostasis resulting in hepatic triglyceride accumulation is an hallmark of NAFLD. This disruption is commonly described based on four pathways concerning 1) increased fatty acid influx, 2) increased de novo lipogenesis, 3) reduced triglyceride secretion, and 4) reduced fatty acid oxidation. More recently, lipophagy has also emerged as pathway affecting NAFLD development and progression. Lipophagy is a form of autophagy (i.e. controlled autolysosomal degradation and recycling of cellular components), that controls the breakdown of lipid droplets in the liver. Here we address the role of hepatic lipid homeostasis in NAFLD and specifically review the current literature on lipophagy, describing its underlying mechanism, its role in pathophysiology and its potential as a therapeutic target.

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Section: Lipophagy: the Fifth Pathway Involved In Non-alcoholic Fattymentioning

confidence: 99%

The Role of Lipophagy in the Development and Treatment of Non-Alcoholic Fatty Liver Disease

et al. 2021

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“…Autophagy is an important lysosome-mediated process for the degradation of cellular components, including damaged organelles and misfolded proteins, for the maintenance of intracellular energy homeostasis (Yang and Klionsky, 2010). Increasing evidence has demonstrated that autophagy is necessary for regulating lipid metabolism because lipid droplets are degraded through lipophagy (Singh et al, 2009;Cui et al, 2020). Disruption of autophagy might therefore contribute to the aggravation of hepatic lipid accumulation (Wu et al, 2020).…”

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confidence: 99%

Liraglutide Alleviates Hepatic Steatosis by Activating the TFEB-Regulated Autophagy-Lysosomal Pathway

Fang

Zhu

et al. 2020

Front. Cell Dev. Biol.

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Liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), has been demonstrated to alleviate non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanism has not been fully elucidated. Increasing evidence suggests that autophagy is involved in the pathogenesis of hepatic steatosis. In this study, we examined whether liraglutide could alleviate hepatic steatosis through autophagy-dependent lipid degradation and investigated the underlying mechanisms. Herein, the effects of liraglutide on NAFLD were evaluated in a high-fat diet (HFD)-induced mouse model of NAFLD as well as in mouse primary and HepG2 hepatocytes exposed to palmitic acid (PA). The expression of the GLP-1 receptor (GLP-1R) was measured in vivo and in vitro. Oil red O staining was performed to detect lipid accumulation in hepatocytes. Electron microscopy was used to observe the morphology of autophagic vesicles and autolysosomes. Autophagic flux activity was measured by infecting HepG2 cells with mRFP-GFP-LC3 adenovirus. The roles of GLP-1R and transcription factor EB (TFEB) in autophagy-lysosomal activation were explored using small interfering RNA. Liraglutide treatment alleviated hepatic steatosis in vivo and in vitro. In models of hepatic steatosis, microtubule-associated protein 1B light chain-3-II (LC3-II) and SQSTM1/P62 levels were elevated in parallel to blockade of autophagic flux. Liraglutide treatment restored autophagic activity by improving lysosomal function. Furthermore, treatment with autophagy inhibitor chloroquine weakened liraglutide-induced autophagy activation and lipid degradation. TFEB has been identified as a key regulator of lysosome biogenesis and autophagy. The protein levels of nuclear TFEB and its downstream targets CTSB and LAMP1 were decreased in hepatocytes treated with PA, and these decreases were reversed by liraglutide treatment. Knockdown of TFEB expression compromised the effects of liraglutide on lysosome biogenesis and hepatic lipid accumulation. Mechanistically, GLP-1R expression was decreased in HFD mouse livers as well as PA-stimulated hepatocytes, and liraglutide treatment reversed the downregulation of GLP-1R expression in vivo and in vitro. Moreover, GLP-1R inhibition could mimic the effect of the TFEB downregulation-mediated decrease in lysosome biogenesis. Thus, our findings suggest that liraglutide attenuated hepatic steatosis via restoring autophagic flux, specifically the GLP-1R-TFEB-mediated autophagy-lysosomal pathway.

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“…Recent results also demonstrated that upon lipophagy, i.e., the specialized form of macroautophagy which is responsible for the degradation of lipid droplets within lysosomes, fatty acids are delivered extracellularly via lysosomal exocytosis [ 148 ]. As these fatty acids are presumably taken up by neighbouring cells, this may represent a mechanism of lipid exchange among cells, for signaling and energy purposes.…”

Section: Lysosomal Exocytosis Associated Functionmentioning

confidence: 99%

Lysosomal Exocytosis: The Extracellular Role of an Intracellular Organelle

et al. 2020

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Lysosomes are acidic cell compartments containing a large set of hydrolytic enzymes. These lysosomal hydrolases degrade proteins, lipids, polysaccharides, and nucleic acids into their constituents. Materials to be degraded can reach lysosomes either from inside the cell, by autophagy, or from outside the cell, by different forms of endocytosis. In addition to their degradative functions, lysosomes are also able to extracellularly release their contents by lysosomal exocytosis. These organelles move from the perinuclear region along microtubules towards the proximity of the plasma membrane, then the lysosomal and plasma membrane fuse together via a Ca2+-dependent process. The fusion of the lysosomal membrane with plasma membrane plays an important role in plasma membrane repair, while the secretion of lysosomal content is relevant for the remodelling of extracellular matrix and release of functional substrates. Lysosomal storage disorders (LSDs) and age-related neurodegenerative disorders, such as Parkinson’s and Alzheimer’s diseases, share as a pathological feature the accumulation of undigested material within organelles of the endolysosomal system. Recent studies suggest that lysosomal exocytosis stimulation may have beneficial effects on the accumulation of these unprocessed aggregates, leading to their extracellular elimination. However, many details of the molecular machinery required for lysosomal exocytosis are only beginning to be unravelled. Here, we are going to review the current literature on molecular mechanisms and biological functions underlying lysosomal exocytosis, to shed light on the potential of lysosomal exocytosis stimulation as a therapeutic approach.

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Lipophagy-derived fatty acids undergo extracellular efflux via lysosomal exocytosis

Cited by 70 publications

References 67 publications

The Role of Lipophagy in the Development and Treatment of Non-Alcoholic Fatty Liver Disease

The Role of Lipophagy in the Development and Treatment of Non-Alcoholic Fatty Liver Disease

Liraglutide Alleviates Hepatic Steatosis by Activating the TFEB-Regulated Autophagy-Lysosomal Pathway

Lysosomal Exocytosis: The Extracellular Role of an Intracellular Organelle

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