Regulation of lipid stores and metabolism by lipophagy

Abstract

Intracellular lipids are stored in lipid droplets (LDs) and metabolized by cytoplasmic neutral hydrolases to supply lipids for cell use. Recently, an alternative pathway of lipid metabolism through the lysosomal degradative pathway of autophagy has been described and termed lipophagy. In this form of lipid metabolism, LD triglycerides (TGs) and cholesterol are taken up by autophagosomes and delivered to lysosomes for degradation by acidic hydrolases. Free fatty acids generated by lipophagy from the breakdown of TGs fuel cellular rates of mitochondrial b-oxidation. Lipophagy therefore functions to regulate intracellular lipid stores, cellular levels of free lipids such as fatty acids and energy homeostasis. The amount of lipid metabolized by lipophagy varies in response to the extracellular supply of nutrients. The ability of the cell to alter the amount of lipid targeted for autophagic degradation depending on nutritional status demonstrates that this process is selective. Intracellular lipids themselves regulate levels of autophagy by unclear mechanisms. Impaired lipophagy can lead to excessive tissue lipid accumulation such as hepatic steatosis, alter hypothalamic neuropeptide release to affect body mass, block cellular transdifferentiation and sensitize cells to death stimuli. Future studies will likely identify additional mechanisms by which lipophagy regulates cellular physiology, making this pathway a potential therapeutic target in a variety of diseases. Open QuestionsHow does the autophagic machinery selectively target stored lipids for degradation in response to changes in nutrient levels? What are the relative contributions of cytosolic lipolysis and lipophagy to lipid metabolism in different cell types, and is there cross-talk between the two pathways? What are the mechanisms by which intracellular lipids and other factors regulate levels of lipophagy? Do defects in lipophagy underlie human disease and can lipophagy be a therapeutic target? Intracellular lipids are essential to cells as an energy source, structural components for membranes, synthetic building blocks for other molecules, such as hormones, and as mediators of cell signaling. The ability to safely store adequate, but not excessive, amounts of lipids and to metabolize them when needed is critical for cell function and survival. The recent finding that lipids can be selectively degraded by the lysosomal pathway of macroautophagy through a process termed lipophagy 1 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 diverse cellular processes ranging from transdifferentiation to resistance to death. Intracellular Lipids are Degraded by LipophagyTGs and cholesterol are safely stored as neutral lipids in specialized cellular organelles called LDs. 2,3 Until recently, the breakdown of LD-stored TG and cholesterol was attributed exclusively to the actions of cytosolic hydrolytic enzymes or lipases. The role of l...

Young plasma reverses age‐dependent alterations in hepatic function through the restoration of autophagy

“…Evidence is also available indicating that excessive steatosis and fibrosis dramatically inhibited hepatic function in various pathological conditions including aging (Kuk et al., 2009). More importantly, autophagy has been reported to be linked to lipid metabolism (Liu & Czaja, 2013; Liu, Guo, et al., 2016; Singh et al., 2009; Yang, Li, Fu, Calay, & Hotamisligil, 2010). Intracellular lipids regulate levels of autophagy, and inhibition of autophagy increases hepatic lipid storage in cultured hepatocytes and mouse liver during starvation (Liu & Czaja, 2013).…”

“…More importantly, autophagy has been reported to be linked to lipid metabolism (Liu & Czaja, 2013; Liu, Guo, et al., 2016; Singh et al., 2009; Yang, Li, Fu, Calay, & Hotamisligil, 2010). Intracellular lipids regulate levels of autophagy, and inhibition of autophagy increases hepatic lipid storage in cultured hepatocytes and mouse liver during starvation (Liu & Czaja, 2013). In our study, the overt steatosis and fibrosis in aged livers were markedly attenuated by young plasma injections, suggesting that young blood may preserve the liver from fibrosis in aging.…”

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“…Although LC3 may be directly recruited to lipid droplets to initiate the formation of a limiting membrane, this idea is controversial 76 . SNARE (SNAP receptor) proteins that have been implicated in both autophagosome biogenesis and lipid droplet fusion may also facilitate macrolipophagy 77 . The identity of the receptors targeting lipids to autophagosomes remains unclear, but recent research has indicated that dynamin 2, a GTPase involved in membrane scission, favours the degradation of hepatic lipid droplets by promoting the maturation of the autophagic compartment 78 .…”

Autophagy: A Crucial Moderator of Redox Balance, Inflammation, and Apoptosis in Lung Disease

“…LC3 can be recruited to LD, suggesting that LD may be selectively removed by autophagy (a process termed lipophagy) (162). The mechanisms of LD sequestration into autophagosomes remain unclear, but they may involve the soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) and LC3, which can associate with LDs in the absence of an autophagosomal membrane (100). Defects in lipophagy may result in altered mitochondrial b-oxidation, along with a failure to supply lipids for structural elements of the cell or to regulate lipid-dependent cell signaling (100).…”