Breaking fat: The regulation and mechanisms of lipophagy

Highlights

• Lipophagy contributes to lipid droplet (LD) degradation in numerous cell types.

• Perilipins, lipases, and Rab GTPases act as key regulators of autophagic/lipophagic initiation.

• Alterations in lipophagy are common in various diseases.

• The mechanisms whereby autophagic machinery target LDs is poorly understood.

• The downstream effects of lipophagy on cell signaling networks are largely unknown.

Abstract

Lipophagy is defined as the autophagic degradation of intracellular lipid droplets (LDs). While the field of lipophagy research is relatively young, an expansion of research in this area over the past several years has greatly advanced our understanding of lipophagy. Since its original characterization in fasted liver, the contribution of lipophagy is now recognized in various organisms, cell types, metabolic states and disease models. Moreover, recent studies provide exciting new insights into the underlying mechanisms of lipophagy induction as well as the consequences of lipophagy on cell metabolism and signaling. This review summarizes recent work focusing on LDs and lipophagy as well as highlighting challenges and future directions of research as our understanding of lipophagy continues to grow and evolve. This article is part of a Special Issue entitled: Recent Advances in Lipid Droplet Biology edited by Rosalind Coleman and Matthijs Hesselink.

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.