Autophagy regulates lipid metabolism
Open accessAbstract
The intracellular storage and utilization of lipids are critical to maintain cellular energy homeostasis. During nutrient deprivation, cellular lipids stored as triglycerides in lipid droplets are hydrolysed into fatty acids for energy. A second cellular response to starvation is the induction of autophagy, which delivers intracellular proteins and organelles sequestered in double-membrane vesicles (autophagosomes) to lysosomes for degradation and use as an energy source. Lipolysis and autophagy share similarities in regulation and function but are not known to be interrelated. Here we show a previously unknown function for autophagy in regulating intracellular lipid stores (macrolipophagy). Lipid droplets and autophagic components associated during nutrient deprivation, and inhibition of autophagy in cultured hepatocytes and mouse liver increased triglyceride storage in lipid droplets. This study identifies a critical function for autophagy in lipid metabolism that could have important implications for human diseases with lipid over-accumulation such as those that comprise the metabolic syndrome.
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In control samples after CPZ-mediated demyelination, large, polymorphic, electron-dense lysosomes (PEDLs) were observed fusing with lipid droplets within phagocytes, which is suggestive of lipophagy.
“In control samples after CPZ-mediated demyelination, large (0.75 μm2 and 1.08 μm2 median areas in CPZ and post-CPZ arms, respectively), polymorphic, electron-dense lysosomes (PEDLs) were observed fusing with lipid droplets within phagocytes, which is suggestive of lipophagy (Figure 3A).”
From Peroxisomal integrity in demyelination-associated microglia enables cellular debris clearance and myelin renewal in mice (2026) · cites this paper as [21]
The Discussion (page unavailable) explicitly says lysosomes do not fuse directly with lipid droplets; they fuse with lipid-droplet-containing autophagosomes instead. The paper supports autophagic delivery of lipid droplets to lysosomes, but it does not report the claimed PEDLs in phagocytes after CPZ-mediated demyelination. (LLM, conf=0.82)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredAutophagy is known to regulate lipid droplet concentrations.
“a mechanism which is known to regulate LD concentrations27–29”
From APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia (2024) · cites this paper as [27]
Mechanisms of lysosomal degradation and autophagy are crucial to remove potentially toxic and protective fatty acids against ER stress-induced cell death.
“The mechanisms of lysosomal degradation and autophagy are crucial to remove potentially toxic and protective fatty acids against ER stress-induced cell death [129,130,131].”
From GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives (2023) · cites this paper as [129]
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- Authors
- Singh, R., Kaushik, S., Wang, Y., Xiang, Y., Novak, I., Komatsu, M., Tanaka, K., Cuervo, A. M., & Czaja, M. J.
- Affiliations
- Albert Einstein College of Medicine (US)
- Tokyo Metropolitan Institute of Medical Science (JP)
- Corresponding author
- Czaja, Mark J.
- Venue
- Nature
- Published
- 2009-04
- Volume
- 458
- Issue
- 7242
- Pages
- 1131-1135
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2676208
- OpenAlex
- W2007505836
- Cited by
- 3,975
- References
- 38
- Citations by year
- 2026: 205 · 2025: 263 · 2024: 296 · 2023: 265 · 2022: 305 · 2021: 330 · 2020: 323 · 2019: 286 · 2018: 270 · 2017: 227 · 2016: 235 · 2015: 221 · 2014: 196 · 2013: 183 · 2012: 139
- FWCI
- 82.52
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (R01AG021904, P01AG031782)
- National Institute of Diabetes and Digestive and Kidney Diseases (K01DK087776, R01DK061498)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- autophagy, lipid droplets, lipid metabolism, nutrient deprivation, starvation, triglyceride storage, lipolysis, autophagosomes, lysosomal degradation, hepatocytes, metabolic syndrome, lipid accumulation
- MeSH terms
- Autophagy-Related Protein 5, Animals, Autophagy, Cell Line, Cholesterol, Dietary Fats, Fatty Acids, Food Deprivation, Lipolysis, Liver, Lysosomes, Microtubule-Associated Proteins, Oxidation-Reduction, Phagosomes, Triglycerides, Hepatocytes, Lipid Metabolism, Mice, Rats
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