Macrolipophagy: Too much fat spoils the autophagic appetite

Lipidomics Gateway (1 May 2009) [doi:10.1038/lipidmaps.2009.1]

Cellular lipid metabolism is regulated by autophagy, a finding with implications for the study of metabolic syndrome

Electron micrograph of cultured hepatocytes showing lipid droplets (LD) with double-membrane inclusions (arrows)

Starvation provokes cells to mobilize energy stores to preserve cellular viability. Triglycerides stored in lipid droplets are hydrolyzed by lipolytic enzymes to supply free fatty acids for oxidation, and cellular components are engulfed by autophagosomes for degradation by the lysosomal pathway. Now, for the first time, in a study by Singh and Kaushik et al. reported in Nature, autophagy has been shown to regulate lipid metabolism. A reciprocal relation between lipid load and autophagic function has potential implications for the study of metabolic syndrome.

Macroautophagy, the major autophagic process, involves highly regulated sequestration of proteins and organelles inside a double-membrane vesicle termed an autophagosome. Fusion with a lysosome leads to degradation of the autophagosome's contents, supplying raw materials for cellular energy production and biosynthesis. Using rat hepatocytes, the authors found that inhibition of autophagy resulted in increased accumulation of triglycerides in the form of lipid droplets. Similarly, activation of autophagy decreased lipid droplet number and triglyceride levels. Lipid accumulation during autophagic inhibition was found to result from blocked lipolysis. A direct association of lipid droplets with an autophagosome marker was revealed by immunofluorescence and by electron microscopy with immunogold staining. Lipid droplets also associated with lysosomal markers but this association, unlike that with autophagosomes, was blocked by inhibition of microtubule function, indicating direct 'autophagoliposome' formation with subsequent lysosomal fusion. In cells cultured in regular medium, components of lipid droplets were detected only in a small portion of autophagosomes; with stimuli for lipid accumulation or increased lipolysis, this proportion greatly increased. The authors propose that basal autophagy includes some lipid droplet content in a non-selective process but that engulfment of lipid droplets can be selectively increased in a switch towards 'macrolipophagy'.

The results from cell culture were borne out in vivo. Lipid droplets in the livers of fed mice did not co-purify with the autophagosome marker LC3-II, but in mice starved for 24 hours lipid droplets did associate with LC3-II; a gradual increase in components of lipid droplets in autophagic compartments began within 6 hours of fasting. Furthermore, a mouse model with impaired autophagy in the liver developed massive lipid accumulation in this organ. Interestingly, mice on a 16 week, high-fat diet had the expected increase in hepatic lipid droplets, but starvation resulted in significantly lower association of lipid droplets with autophagosomes. In concert with an absence of autophagic upregulation in hepatocytes cultured with lipids and impaired autophagic clearance in these cells, these results indicate that increased lipid accumulation, beyond physiological levels, impairs autophagic function.

This study does not suggest that all lipid droplets must fuse with autophagosomes for lipid hydrolysis to take place: blockage of autophagy partly prevents triglyceride oxidation compared with total prevention by inhibition of lipolysis. However, autophagy clearly has a regulatory role in lipid metabolism. Lipid accumulation can inhibit this role, decreasing autophagic function and promoting further lipid accumulation in a harmful feedback cycle. Hepatic lipid accumulation occurs in aged humans, along with an increased incidence of metabolic syndrome. Because autophagic activity in the liver decreases with age, the interplay between lipid accumulation and autophagic function may contribute to development of the metabolic syndrome, which suggests that autophagic function could be a novel target of preventative therapy for metabolic syndrome and its associated pathologies.

Emma Leah