Classical and alternative roles for autophagy in lipid metabolism

Abstract

Purpose of review: Intracellular lipid metabolism is a complex interplay of exogenous lipid handling, trafficking, storage, lipolysis, and export. Recent work has implicated the cellular degradative process called autophagy in several aspects of lipid metabolism. We will discuss both the classical and novel roles of autophagy and the autophagic machinery in this setting.

Recent findings: The delivery of lipid droplets to lysosomes for hydrolysis, named lipophagy, was the first described functional role for autophagy in lipid metabolism. The molecular machinery and regulation of this selective form of macroautophagy is beginning to be discovered and has the potential to shed enormous light on intracellular lipolysis. Yet, the autophagic machinery appears to also be coopted for alternative roles that include interaction with cytosolic lipolysis pathways, supply and expansion of lipid droplets, and lipoprotein trafficking. Additionally, lesser studied forms of autophagy called microautophagy and chaperone-mediated autophagy have distinct roles in lipid handling that also intersect with classical macroautophagy. The integration of current knowledge in these areas into a holistic understanding of intracellular lipid metabolism will be a goal of this review.

Summary: As the field of autophagy has evolved and expanded to include functional roles in various aspects of cellular degradation, so has its role in intracellular lipid metabolism. Understanding the mechanisms underlying these classical and alternative roles of autophagy will not only enhance our knowledge in lipid biology but also provide new avenues of translation to human lipid disorders.

FIGURE 1

Overview of autophagic processes. Macroautophagy involves engulfment of cargo in a double membrane phagosome, which fuses with a lysosome to deliver contents for subsequent hydrolysis. In CMA, the adapter molecule HSC70 binds to the KFERQ motif in target proteins for translocation to the lysosome, where proteins enter directly through lysosome-associated membrane protein 2a for degradation. Microautophagy involves direct invagination of the lysosomal membrane for engulfment of cytosolic contents.

FIGURE 2

Microlipophagy: ATG32 and ATG21 are required for formation of liquid-ordered microdomains, the site of lipid droplet internalization at the lysosome/vacuole surface. ATG14p and ATG6p localize to liquid-ordered microdomains and are involved in their expansion and lipid droplet internalization. The molecular machinery of lipophagy. Macrolipophagy: A variety of mechanisms recruit the autophagosome to the lipid droplet for engulfment and delivery to the lysosome. (Left) The GTPase Rab7 directly facilitates lipophagy and also recruits Rab10 to the lipid droplet. Rab10 forms a complex with EHBP1 and EHD2 to initate lipophagy, potentially through membrane elongation along the LD surface. (Center) The lipid droplet surface protein PLIN2 can bind p62, a selective autophagy chaperone which binds LC3 on autophagosomes. (Right) AUP1 recruits the ubiquitin ligase Ube2g2 which ubiquitinates LD surface proteins. This ubiquitination may facilitate lipophagy through to-be-determined selective autophagy adapter binding to autophagosomes. ATG, autophagy-related; LC3, light chain 3; PLIN2, perilipin 2; Ube2g2, ubiquitin conjugating enzyme E2 G2.

FIGURE 3

Regulation of lipophagy: (a) With high nutrient availability, mTOR is active and AMPK is inactive, resulting in reduced ULK1 activity and lack of autophagy/lipophagy initiation. mTOR also inactivates transcription factors including TFEB and TFE3 to prevent their transcriptional targeting of autophagy-lysosome genes. Lipophagy is also subject to transcriptional repression by FXR and epigenetic repression by LSD1. (b) In the fasted state, mTOR is inactive and AMPK is active, resulting in full ULK1 activity and initiation of autophagy/lipophagy. Further, transcriptional regulation of autophagy and lipophagy is fully engaged by a set of transcription factors including TFEB, TFE3, CREB, and FOXO. Beta adrenergic signaling induces lipophagy transcriptionally through activating PKA and CREB. AMPK, adenosine monophosphate-activated protein kinase; FOXO, forkhead box-O; FXR, farnesoid-X receptor; LSD1, lysine-specific histone demethylase 1; PKA, protein kinase A; TFEB, transcription factor EB.

FIGURE 4

Alternative Roles for Autophagy in Lipid Metabolism (a) Chaperone-mediated autophagy targets PLIN2/3 for lysosomal degradation, allowing the machineries of lipophagy and cytosolic lipolysis to access lipid droplets. (b) Cytosolic lipases (ATGL/HSL) require binding to LC3 on the cytoplasmic face of autophagosomes for recruitment to the lipid droplet and activity. Autophagosomes also serve as scaffolds for MEK/ERK signaling activation of lipolysis. ATGL drives SIRT1-mediated induction of autophagy. (c) During starvation, autolysosomes deliver FFA to the ER for esterification and DGAT1-mediated TG synthesis to build lipid droplets. Subsequent cytosolic lipolysis at the LD fuels mitochondrial beta oxidation. (d). Autophagy clears aggregated and/or oxidatively modified ApoB, limiting secretion. Independently, Sortilin targets ApoB for autophagic degradation, limiting LDL formation and secretion. ApoB, apolipoprotein B; DGAT1, diacylglycerol O-acyltransferase 1; LC3, light chain 3; PLIN2, perilipin 2.