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Cell biology

Another way to get rid of fat

When starved, cells resort to breaking down their assets — proteins, lipids and even whole organelles. An investigation of lipid metabolism indicates that one process — autophagy — targets all three cellular components.

Fatty acids are essential to all organisms — as substrates for energy production, as precursors of membrane lipids and as signalling molecules that control various cellular processes, including gene expression. They are stored as triglycerides in highly dynamic organelles called lipid droplets1 and, when necessary, are re-released by the process of lipolysis. Established models of lipid storage and breakdown have undergone substantial revision in recent years. The latest adjustment is offered by Singh et al.2 (page 1131 of this issue): their spectacular findings suggest that autophagy, the pathway by which excess or damaged organelles and proteins are degraded3, also mediates fat mobilization and breakdown in liver cells (hepatocytes).

A rapid flux of fatty acids into and out of lipid droplets occurs through the deposition and degradation of triglycerides in adipose tissue and in other tissues (liver, heart, muscle and testis) and cells (macrophages) that require abundant fatty acids. Hydrolytic enzymes called lipases mediate lipid breakdown (catabolism), and for 40 years it was believed that hormone-sensitive lipase (HSL) acted alone in the catabolism of triglycerides. But the discovery of other essential lipases, such as ATGL, and regulatory proteins, including perilipin and CGI-58, indicated that the lipolytic pathway is much more complex than that4.

In fact, key aspects of lipid turnover remain unclear. One mystery is the rapid turnover of triglycerides and cholesteryl esters (another component of lipid droplets) in hepatocytes, despite the cells' low concentrations of HSL and ATGL. By presenting compelling evidence for an autophagic mechanism mediating fasting-induced lipolysis in both mouse liver and culture-grown hepatocytes, Singh et al. resolve some of these issues.

In autophagy, cytoplasmic components and cellular organelles destined for degradation become trapped in double-membrane-bound vesicles called autophagosomes, and are then broken down in lysosomes with which the autophagosomes fuse3. This sequestration and lysosomal breakdown of autophagosomal contents is generally referred to as macroautophagy.

In a functional analogy to macroautophagy, Singh et al.2 show that, under fasting conditions, the cytoplasmic protein LC3 and several other autophagy-related proteins are recruited to lipid droplets, where they form a double membrane that encloses droplet parts. These lipid-containing vesicles, termed autolipophagosomes, subsequently fuse with lysosomes, and their contents are degraded (Fig. 1).

Figure 1: Lipolysis and autophagy.
figure1

Activation of intracellular signalling pathways mediated by the hormones glucagon and catecholamines can trigger the hydrolysis of triglycerides to fatty acids in lipid droplets by the process of lipolysis, which is mediated by lipase enzymes. Singh and co-authors2 demonstrate that, during fasting, one such pathway in the liver involves TOR kinase and ATG proteins, and results in fatty-acid generation by an alternative mechanism. In a process they call macrolipophagy, portions of lipid droplets, or even whole droplets, become trapped inside the double-membrane-bound autolipophagosome vesicles and are transported to lysosomes, where they are degraded to fatty acids. Both lipolysis and macrolipophagy are inhibited by the hormone insulin.

The authors also show that the efficiency of this process of 'macrolipophagy' varies with the nutritional status of the mice. Feeding the animals a high-fat diet for an extended period (16 weeks) impairs autophagy-mediated breakdown of lipid stores in the liver, inducing a vicious circle in which — as the authors propose — increased fat ingestion may be associated with decreased fat removal and excessive lipid deposition in the liver. A similar response in obese people would explain how they might develop fatty-liver disease. Additionally, autophagy diminishes with age, possibly explaining the age-related deposition of fat in tissues where it does not belong. Singh and colleagues' results therefore provoke speculation that inducing autophagy through drug-mediated inhibition of TOR kinase, its master regulator protein, might ameliorate diet- or age-induced fatty-liver disease in humans. Intriguingly, resveratrol — a potent inducer of autophagy found naturally in red wine5 — prolongs the lifespan of mice fed a high-calorie diet6.

It remains to be seen how extensively macrolipophagy contributes to lipid homeostasis under physiological conditions, and whether it is involved in fat mobilization in adipose tissue. Another question relates to the role of macrolipophagy in the hydrolysis of cholesteryl esters in macrophages. Accumulation of cholesterol and cholesteryl esters in these cells leads to the formation of foam cells — an early indicator of atherosclerosis. Autophagy-facilitated hydrolysis of cholesteryl esters might mobilize cholesterol from lipid droplets and initiate its transport to the liver, a process called reverse cholesterol transport.

Moreover, the effect of autophagy on cellular lipid homeostasis is probably complex, and may not be restricted to macrolipophagy, because indirect contributions from the autophagy of cellular organelles such as mitochondria and peroxisomes are certainly possible. In their experiments, Singh et al.2 deleted the gene encoding ATG7, a protein that probably affects all forms of macroautophagy. So the effects they observed on lipid homeostasis in the liver of mice lacking ATG7 may be multifactorial and not necessarily restricted to defective macrolipophagy alone. Accordingly, it is essential to determine the contribution of different subtypes of autophagy to lipid and energy homeostasis.

The exact mechanism of autolipophagosome assembly and the vesicles' subsequent fate also require detailed investigation. For instance, lipolytic hormones such as catecholamines cause lipid droplets to break down into smaller particles, streamlining fat catabolism in adipose tissue7. Is autolipophagosome formation the mechanism by which lipid-droplet fragmentation occurs?

Another question relates to the lipases that mediate autolipophagosome degradation. Lysosomal acid lipase is the only triglyceride and cholesteryl ester hydrolase enzyme known to exist in lysosomes and is therefore predicted to degrade these lipid ester components of autolipophagosomes. This enzyme also catabolizes the lipid components of internalized lipoproteins. Deficiency of lysosomal acid lipase causes Wolman's disease, a disorder characterized by the accumulation of triglycerides and cholesteryl esters in various tissues, and resulting in premature death. Excessive lipid storage in these patients might thus arise from defective breakdown of both external lipoproteins and lipid droplets in lysosomes. Notably, lipid-containing cytoplasmic particles have been observed in hepatocytes of both a rat model of Wolman's disease8 and patients with liver disease9; these particles could be unprocessed autolipophagosomes.

Finally, the exact role of LC3 must be established. Whereas Singh et al. show that this protein is essential for the formation of autolipophagosomes and for lipolysis, another study10 has found that it is involved in lipid and lipid-droplet formation.

Macrolipophagy adds another level of complexity to the breakdown of fat during fasting. In addition to lipase-mediated lipolysis, this process offers an alternative target for the control of fat breakdown in hepatocytes and possibly other cells and organs. Beside the potential for drug intervention, it is worth remembering that an old adage of innumerable human cultures holds that fasting offers the best protection from various diseases, including metabolic disorders. Macrolipophagy might be a crucial component of this widespread practice.

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Zechner, R., Madeo, F. Another way to get rid of fat. Nature 458, 1118–1119 (2009). https://doi.org/10.1038/4581118a

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