Cholesterol depletion induces autophagy

Cheng, Jinglei; Ohsaki, Yuki; Tauchi-Sato, Kumi; Fujita, Akikazu; Fujimoto, Toyoshi

doi:10.1016/j.bbrc.2006.10.042

Cited by 112 publications

(102 citation statements)

References 26 publications

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“…An acute cholesterol stimulus such as AcLDL loading in macrophages, 52 or free cholesterol treatment of smooth muscle cells, 83 increased autophagy. Alternatively, cholesterol 84 and sterol 85 depletion have also been reported to increase autophagy. Potentially, autophagy functions to both rid the cell of excessive cholesterol and break down LDstored cholesterol in times of deprivation.…”

Section: Levels Of Autophagy Are Altered By Cellular Lipid Contentmentioning

confidence: 99%

Regulation of lipid stores and metabolism by lipophagy

2012

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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...

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Section: Levels Of Autophagy Are Altered By Cellular Lipid Contentmentioning

confidence: 99%

Regulation of lipid stores and metabolism by lipophagy

2012

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“…Since itraconazole possesses the potential to suppress the biosynthesis of cholesterol, and cholesterol depletion can induce autophagy through AKT1-MTOR inhibition, 34,35 we addressed whether itraconazole-induced autophagy was mediated by decreased cholesterol levels. As shown in Figure 7A, treatment with 5 μM itraconazole, which was capable of triggering autophagy ( Fig.…”

Section: Itraconazole-induced Cholesterol Redistribution Triggers Autmentioning

confidence: 99%

Itraconazole suppresses the growth of glioblastoma through induction of autophagy

et al. 2014

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“…We found an early onset increase in autophagic activity in brain of a mouse model of Niemann-Pick Type C disease, a disease characterized by impairment in intracellular cholesterol trafficking and accumulation of cholesterol and other lipids in late endosomes and lysosomes. [12][13][14] Cholesterol depletion, either by acute extraction or synthesis inhibition, induces autophagy 15,16 suggesting that "lipid starvation" may also lead to autophagy. Whether "lipid starvation" contributes to the autophagic activity observed in brains of Npc1 -/-mice remains to be determined.…”

Section: Constitutive Autophagy and Reactive Autophagy In Mammalian Bmentioning

confidence: 99%

Autophagic-Lysosomal Dysfunction and Neurodegeneration in Niemann-Pick Type C Mice: Lipid Starvation or Indigestion?

Liao²

2007

Autophagy

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Cholesterol depletion induces autophagy

Cited by 112 publications

References 26 publications

Regulation of lipid stores and metabolism by lipophagy

Regulation of lipid stores and metabolism by lipophagy

Itraconazole suppresses the growth of glioblastoma through induction of autophagy

Autophagic-Lysosomal Dysfunction and Neurodegeneration in Niemann-Pick Type C Mice: Lipid Starvation or Indigestion?

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