Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
ReviewBreaking fat: The regulation and mechanisms of lipophagy☆
Introduction
LDs represent the most energetically dense and, often, primary form of energy storage in most cell types. These dynamic organelles form and expand or shrink and dissolve in response to changes in energy status of cells. In times of energy demand, fatty acids (FAs) liberated from LD-containing triacylglycerol (TAG) degradation are substrates for β-oxidation and ultimately the generation of ATP needed for cell survival. On an organism level, LD degradation in white adipose tissue (WAT) is critical to increase circulating FAs that provide fuel in non-adipose tissues during nutrient insufficiency. Although LDs have historically been recognized for their importance in energy storage, a growing body of literature has more recently identified important roles in cell signaling and function that link LD accumulation to the etiology of numerous diseases [1]. Thus, the LD represents a dynamic organelle that serves a multitude of functions.
Historically, the degradation of TAG and cholesterol ester (CE) stored within LDs was attributed to the actions of hormone-sensitive lipase (HSL) as first discovered over a half-century ago [2], [3]. Subsequent work has revealed that HSL primarily hydrolyzes diacylglycerol, in addition to CE, which led to additional studies that ultimately identified adipose triglyceride lipase (ATGL) as the primary cytosolic lipase in numerous metabolically active tissues including adipose, heart, liver and intestine [4], [5], [6]. In response to lipolytic stimuli, ATGL is recruited to LDs to facilitate the initial step in TAG catabolism followed by subsequent reactions catalyzed by HSL and monoacylglycerol lipase. Until the discovery of lipophagy, this pathway was thought to be the primary mechanism through which TAG contained within LDs was degraded.
Although the effects of autophagy on degradation of various organelles has been known since the early 1960s [7], [8], only recently has the contribution of autophagy to LD degradation been identified. Putative links between autophagy and LDs arose following the observation that mutations in lysosomal acid lipase (LAL), which is responsible for lysosomal lipid degradation, leads to the accumulation of LDs in various organs [9], [10], [11]. Indeed, LAL enzymatic insufficiency is the cause of Wolman Disease and Cholesterol Ester Storage Disease (CESD). However, because of the concomitant lipodystrophy and reduced hepatic catabolism of endocytosed lipoproteins in subjects lacking functional LAL, the contribution of lipophagy to LD accumulation was not known. A groundbreaking study by Singh et al. in 2009 clearly demonstrated in hepatocytes that autophagy contributes to the degradation of LDs, leading to the origin of the term “lipophagy” [12]. Similar to non-specific canonical autophagy, the selective process of lipophagy can occur via both macro- and micro- based mechanisms. Macrolipophagy involves the classical autophagosome-mediated pathway of budding off and sequestering LDs for their subsequent delivery to autolysosomes. Microlipophagy reflects the direct and transient interactions of lysosomes with LDs as a means to degrade LD-derived lipids. Chaperone-mediated autophagy (CMA), another arm of autophagy involving targeted protein degradation, is not directly responsible for LD degradation, but may influence lipophagy indirectly as discussed below.
Section snippets
PLINs and lipases
Although LDs differ in lipid composition, size, and cellular location, perhaps the characteristic that best highlights their dynamic nature is their proteome. The surface of the LDs comprises hundreds of resident and transient proteins that influence LD metabolism and signaling. An emerging role of these proteins is to regulate LD-specific functions including lipophagy. The perilipin family members are the best characterized LD proteins and play numerous roles in LD biology [13]. This family of
Lysosomal lipid degradation
Once internalized into the lysosome, LAL is responsible for the hydrolysis of TAG and CE. LAL is perhaps most recognized for its deficiency, which results in Wolman disease and CESD [67], [68]. Mutations in LAL that render the enzyme catalytically dead result in the more severe Wolman Disease, where some residual activity remains in mutations that lead to CESD. Clinical manifestations of Wolman disease include massive accumulation of TG and CE in the liver and spleen, intestinal malabsorption,
Transcriptional regulation
The past few years have brought major advances in our understanding into the transcriptional control of autophagy and, to some degree, lipophagy. The most studied transcriptional regulators of autophagy/lipophagy are the members of the microphthalmia-associated/TFE subfamily of basic/helix-loop-helix/leucine zipper transcription factors that include TFEB and TFE3 in mammals and HLH-30 in C. elegans. In addition to activating peroxisome proliferator-activated receptor (PPAR)-γ coactivator 1α
Fatty liver disease
The finding that autophagy serves a central role in hepatic lipid homeostasis [12] has resulted in numerous studies focused on elucidating the contribution of this catabolic process to the onset of non-alcoholic fatty liver disease (NAFLD). NAFLD is estimated to have a global prevalence of nearly 25% in adults and represents the second leading indication for liver transplant in the United States [100]. A great deal remains to be understood regarding potential connections between human liver
Relevance of Lipophagy to cellular signaling
Once internalized in lysosomes, complex lipids such as TAG, phospholipids and CEs are hydrolyzed to simple lipids such as FAs and cholesterol. Fatty acids have diverse signaling roles including ligands for transcription factors, allosteric modulators and substrates for the generation of other signaling molecules (i.e. eicosanoids, sphingolipids, etc.). Cholesterol also has diverse signaling effects, although perhaps the most noted is its negative feedback regulation of SREBP2 to control the
Lipophagic targeting of LDs
The past several decades of autophagy research have largely involved characterizing the core proteins and signaling networks that govern the global autophagy pathway. Given the breadth of substrates that undergo autophagic degradation, a current and future focus of the field will be to identify and characterize specific proteins and signaling networks that facilitate the individual arms of autophagy such as lipophagy. While numerous proteins (Rabs, etc.) involved in lipophagy have been
Conclusions
Despite its relative youth compared to autophagy, the field of lipophagy has seen tremendous growth and major advances in the past several years. The identification of a subset of proteins crucial for the initiation of lipophagy has facilitated a better understanding of the core components that help the autophagic machinery recognize and degrade LDs. In addition, we have made significant strides in our understanding of the transcriptional networks that govern both lipophagy and autophagy. While
Funding
This work was supported by a NIH grants T32DK007352 (R.J.S.), DK108790 (D.G.M) and DK050456 (Minnesota Obesity Center), and a grant from the American Diabetes Association (1-16-IBS-203) to D.G.M.
Conflict of interest
The authors declare no conflict of interest.
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This article is part of a Special Issue entitled: Recent Advances in Lipid Droplet Biology edited by Rosalind Coleman and Matthijs Hesselink.