The regulation, function, and role of lipophagy, a form of selective autophagy, in metabolic disorders

Abstract

Autophagy is a conserved method of quality control in which cytoplasmic contents are degraded via lysosomes. Lipophagy, a form of selective autophagy and a novel type of lipid metabolism, has recently received much attention. Lipophagy is defined as the autophagic degradation of intracellular lipid droplets (LDs). Although much remains unknown, lipophagy appears to play a significant role in many organisms, cell types, metabolic states, and diseases. It participates in the regulation of intracellular lipid storage, intracellular free lipid levels (e.g., fatty acids), and energy balance. However, it remains unclear how intracellular lipids regulate autophagy. Impaired lipophagy can cause cells to become sensitive to death stimuli and may be responsible for the onset of a variety of diseases, including nonalcoholic fatty liver disease and metabolic syndrome. Like autophagy, the role of lipophagy in cancer is poorly understood, although analysis of specific autophagy receptors has helped to expand the diversity of chemotherapeutic targets. These studies have stimulated increasing interest in the role of lipophagy in the pathogenesis and treatment of cancer and other human diseases.

Fig. 1. The lipolysis and lipophagy pathways of lipid droplets.

a Chaperone-mediated autophagy degrades the LD coat proteins perilipin 2 and perilipin 3 through the coordinated action of heat-shock cognate 71 kDa protein (HSC70) and receptor lysosome-associated membrane glycoprotein 2A (LAMP2A). b Degradation of the LD coat proteins PLP2 and PLP3 allows lipase- and fat-soluble organelles to enter and undergo lipolysis. c Lipophagy induces engulfment of small cytoplasmic lipid droplets or large cytoplasmic lipid droplets by LC3-II-positive membranes. Lipid droplets are transported to lysosomes and degraded by lysosomal acid lipase (LAL). Rab7 promotes the decomposition of LDs by interacting with its downstream effector RILP. The fatty acids produced are mainly directed to the mitochondria to participate in the β-oxidation pathway.

Fig. 2. Autophagy in mammalian cells.

The initiation of autophagy is dependent on six distinct protein complexes formed by the following proteins: ULK1, class III PI3K (phosphoinositide 3-kinase), ATG9, ATG2-ATG18, ATG8/LC3, and ATG12.

Fig. 3. Lipolysis and lipophagy may be sequential pathways.

A Larger lipid droplets cannot be degraded by lipophagy and need to be degraded by ATGL-driven lipolysis. Lipolysis can reduce the size of lipid droplets. Some LDs escape β-oxidation in the endoplasmic reticulum and become esterified into small lipid droplets by DGAT1/2, at which point they are degraded via lipophagy. Lipolysis and lipophagy may be sequential pathways. B Synergistic degradation of the lipid droplet coat proteins PLIN2 and PLIN3 occurs via heat-shock protein (HSC70) and receptor lysosome-associated membrane glycoprotein 2A (LAMP2A).

Fig. 4. Lipophagy alters cell death responses.

a, b Oxidative stress decreases the rate of mitochondrial β-oxidation, resulting in a decrease in cell ATP content. Severe reductions in ATP can lead to necrosis and cell death. Decreased levels of ATP promote mitochondrial dysfunction and trigger apoptotic cell death by affecting the release of cytochrome c. Lipophagy mediates resistance to these two forms of cell death by degrading lipid droplets into fatty acids and participating in the synthesis of ATP. c Lipotoxic molecules can cause apoptosis directly or by inhibiting lipophagy, which degrades lipotoxic molecules by enveloping triglycerides in lipid droplets and degrading them.