Lipophagy: connecting autophagy and lipid metabolism

Abstract

Lipid droplets (LDs), initially considered "inert" lipid deposits, have gained during the last decade the classification of cytosolic organelles due to their defined composition and the multiplicity of specific cellular functions in which they are involved. The classification of LD as organelles brings along the need for their regulated turnover and recent findings support the direct contribution of autophagy to this turnover through a process now described as lipophagy. This paper focuses on the characteristics of this new type of selective autophagy and the cellular consequences of the mobilization of intracellular lipids through this process. Lipophagy impacts the cellular energetic balance directly, through lipid breakdown and, indirectly, by regulating food intake. Defective lipophagy has been already linked to important metabolic disorders such as fatty liver, obesity and atherosclerosis, and the age-dependent decrease in autophagy could underline the basis for the metabolic syndrome of aging.

Figure 1

Lipolysis of lipid droplets. (a) Schematic representation of the main lipid and protein components of lipid droplets (LDs) and mechanisms of lipid mobilization (lipolysis) by cytosolic lipases. (b) Lipolysis by lipophagy. Schematic representation of the formation of autophagic vacuoles at the surface of an LD. PLIN: perilipin; Atg: autophagy-related protein; FFA: free fatty acids.

Figure 2

Autophagy and lipid metabolism in liver. (a) Basal lipophagy: some level of mobilization of LD by autophagy occurs continuously in all tissues including the liver. (b) Inducible lipophagy: stimuli such as prolonged starvation or maintained lipid challenges induce liver lipophagy to regulate LD growth. Failure to upregulate autophagy under these conditions could results in liver steatosis. (c) Lipogenesis/lipolysis balance: autophagy may also contribute to LD formation by mechanisms still unknown. A partial blockage of the autophagic process may modify the lipogenic-lipolytic balance in one direction or another depending on the cellular conditions.

Figure 3

Conceptual model for hypothalamic lipophagy in control of food intake. In the fed state, active PI3K/mTOR signaling maintains autophagy at basal lower levels. Starvation increases circulating free fatty acids (FFAs), which activate hypothalamic autophagy by mechanisms that may in part require activation of AMPK/ULK1. These FFAs taken up by hypothalamic neurons are rapidly esterified into neutral lipids within lipid droplets. Activation of hypothalamic autophagy mobilizes neuronal lipids for the controlled availability of neuron-intrinsic FFAs that increase AgRP expression and food intake. AgRP: Agouti-related peptide, AMPK: AMP-activated protein kinase, FFA: free fatty acids, LD: lipid droplets, PI3K: phosphoinositide 3-kinase, mTOR: mammalian target of rapamycin, and ULK1: unc-51-like kinase 1.

Figure 4

Lipophagy in pathology and aging. Alterations in the autophagic system and in its ability to mobilize intracellular lipids may underline the basis of important human disorders. The possible links of lipophagic malfunctioning with obesity, atherosclerosis, and the metabolic syndrome of aging are depicted.