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  • Review Article
  • Published:

Cytosolic lipolysis and lipophagy: two sides of the same coin

Nature Reviews Molecular Cell Biology volume 18, pages 671–684 (2017)Cite this article

Subjects

Key Points

  • This Review focuses on the pathways that catabolize cellular triacylglycerol ('fat'), namely, neutral lipolysis, acid lipolysis and lipophagy.

  • Neutral lipolysis of triglycerides in cytosolic lipid droplets relies on three lipid hydrolases (lipases): adipose triglyceride lipase, hormone-sensitive lipase and monoacylglycerol lipase. The consecutive action of these enzymes provides free fatty acids and glycerol for energy production and other metabolic pathways during fasting. The regulation of neutral lipolysis is complex and involves numerous proteins, hormones, growth factors and cytokines. Conversely, products and intermediates of neutral lipolysis regulate key metabolic pathways by transcriptional and post-transcriptional mechanisms.

  • Lipophagy is a subtype of macroautophagy. Portions of cytosolic lipid droplets are engulfed by lipoautophagosomes and transported to lysosomes, where triacylglycerols and other lipids undergo acid lipolysis by lysosomal acid lipase.

  • The regulation of acid lipolysis is less complex than the regulation of neutral lipolysis, but again, the products and intermediates of triacylglycerol hydrolysis exit lysosomes and regulate multiple key processes in energy metabolism.

  • Neutral lipolysis, acid lipolysis and lipophagy cooperate mechanistically.

  • Rare mutations in the genes coding for adipose triglyceride lipase; its co-activator, lipid droplet-binding protein CGI-58; hormone-sensitive lipase; and lysosomal acid lipase cause distinct metabolic disorders in humans.

  • Recent insights led to a better understanding of how cellular triacylglycerol catabolism affects the pathogenesis of metabolic diseases, cancer and cancer-associated cachexia and highlighted potential treatment strategies for lipid-associated disorders.

Abstract

Fatty acids are the most efficient substrates for energy production in vertebrates and are essential components of the lipids that form biological membranes. Synthesis of triacylglycerols from non-esterified free fatty acids (FFAs) combined with triacylglycerol storage represents a highly efficient strategy to stockpile FFAs in cells and prevent FFA-induced lipotoxicity. Although essentially all vertebrate cells have some capacity to store and utilize triacylglycerols, white adipose tissue is by far the largest triacylglycerol depot and is uniquely able to supply FFAs to other tissues. The release of FFAs from triacylglycerols requires their enzymatic hydrolysis by a process called lipolysis. Recent discoveries thoroughly altered and extended our understanding of lipolysis. This Review discusses how cytosolic 'neutral' lipolysis and lipophagy, which utilizes 'acid' lipolysis in lysosomes, degrade cellular triacylglycerols as well as how these pathways communicate, how they affect lipid metabolism and energy homeostasis and how their dysfunction affects the pathogenesis of metabolic diseases. Answers to these questions will likely uncover novel strategies for the treatment of prevalent metabolic diseases.

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Figure 1: Overview of the enzymes involved in lipolysis and the potential functions of their enzymatic products.
Figure 2: Direct and indirect regulation of the lipases involved in neutral and acid lipolysis.
Figure 3: Common regulation of neutral lipolysis and lipophagy.
Figure 4: Autophagy, lipophagy, lipolysis and their crosstalk.

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Acknowledgements

Financial support was provided by the European Research Council ERC Grant Agreement 340896, LipoCheX (R.Z.), the DKs Molecular Enzymology (W901) (R.Z.) and Metabolic and Cardiovascular Disease (W1226) (F.M., D.K.), the SFB Lipotox (F30) funded by the Austrian Science Fund (FWF) (R.Z., F.M., D.K.), the Louis-Jeantet Foundation (R.Z.), the Fondation Leducq (grant 12CVD04) (R.Z.) and the BioTechMed-Graz flagship projects EPIAge (F.M.) and Lipid Signalling (D.K.). F.M. acknowledges additional support from NAWI Graz; BioTechMed-Graz (“EPIAge”); FWF grants P29262, P29203 and P27893; and the BMWFW and University of Graz grants “Unkonventionelle Forschung” and “Flysleep”.

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Authors and Affiliations

  1. BioTechMed-Graz, Mozartgasse 12, Graz, 8010, Austria

    Rudolf Zechner, Frank Madeo & Dagmar Kratky

  2. Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, Graz, 8010, Austria

    Rudolf Zechner & Frank Madeo

  3. Institute of Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6/6, Graz, 8010, Austria

    Dagmar Kratky

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  1. Rudolf Zechner
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Researching the literature for the article: R.Z., F.M. and D.K.; substantial contributions to discussion of the content: R.Z., F.M. and D.K.; writing: R.Z. and D.K.; review and/or editing of the manuscript before submission: R.Z., F.M. and D.K.

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Correspondence to Rudolf Zechner.

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Glossary

Fatty acids

Monocarboxylic acids with long saturated or unsaturated aliphatic carbon chains. They are either unesterified, in free form (free fatty acids) or esterified to various alcohols.

Acid–base homeostasis

Maintenance of a constant pH in extracellular body fluids by balanced concentrations of acids and bases.

White adipose tissue

(WAT). A loose connective tissue that predominantly consists of adipocytes and that stores excess nutrients as triacylglycerols.

Very-low-density lipoproteins

(VLDL). Liver-derived plasma lipoproteins of very low density that transport lipids (predominantly triacylglycerols) from the liver to non-hepatic tissues.

Chylomicrons

Intestine-derived plasma lipoproteins that transport dietary lipids (predominantly triacylglycerols) from the digestive tract (intestine) to the liver and other tissues.

Lipases

Enzymes that hydrolyse fatty acid–glycerol esters.

Patatin-like phospholipase domain-containing protein 2

(PNPLA2). A protein with a patatin domain that hydrolyses neutral lipids, phospholipids and retinyl esters.

Patatin domain

A protein domain of approximately 180 amino acids in length that was originally discovered in the potato tuber storage protein patatin.

Brown adipose tissue

Adipose tissue involved in thermoregulation, uncoupling mitochondrial electron transport from ATP synthesis and thereby generating heat during chronic cold exposure.

sn

A notation that stands for 'stereospecific numbering' and describes the stereochemical configuration of chiral glycerol derivatives.

Endocannabinoid signalling

Signalling that comprises cannabinoid receptors and their endogenous ligands, which regulate numerous physiological processes, including energy homeostasis, pain perception, inflammation and tumorigenesis.

Catecholamines

Tyrosine derivatives of catechol, including adrenaline, noradrenaline and dopamine, that act as neuromodulators and hormones.

Natriuretic peptides

Peptides that control the homeostasis of water, sodium and potassium in the body. In adipocytes, these peptides also regulate lipolysis.

Scavenger receptors

Lipoprotein receptors that remove modified lipoproteins (for example, acetylated or oxidized low-density lipoproteins) and other negatively charged macromolecules from the blood.

Kupffer cells

Specialized macrophages in the liver.

Foam cell

A lipid-filled macrophage that is present in atherosclerotic lesions and plaques.

Steatosis

A process describing the abnormal retention of neutral lipids (triacylglycerols and cholesteryl esters) within cells and tissues.

Fatty liver disease

A reversible condition characterized by the excessive accumulation of neutral lipids in the liver. This condition can be subdivided into alcoholic fatty liver disease and non-alcoholic fatty liver disease.

Cachexia

A wasting syndrome characterized by an unintentional and nutritionally irreversible loss of body mass (muscle and fat mass). Various chronic diseases can lead to cachexia, but it is most common in cancer.

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Zechner, R., Madeo, F. & Kratky, D. Cytosolic lipolysis and lipophagy: two sides of the same coin. Nat Rev Mol Cell Biol 18, 671–684 (2017). https://doi.org/10.1038/nrm.2017.76

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