ATGL Promotes Autophagy/Lipophagy via SIRT1 to Control Hepatic Lipid Droplet Catabolism

Sathyanarayan, Aishwarya; Mashek, Mara T.; Mashek, Douglas G.

doi:10.1016/j.celrep.2017.03.026

Cited by 266 publications

(231 citation statements)

References 39 publications

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“…In one of the seminal studies by Kaushik et al ., the authors showed that the ATGL‐catalyzed lipolysis in the liver involved the degradation of the LD proteins perilipin 2 and 3 (PLIN2 and 3) through CMA . Another report highlighted the role of ATGL‐mediated LD catabolism in the liver that involved SIRT1 as the primary mechanism for lipophagy and fatty acid oxidation . Pertinent to our observation, a recent study highlighted the role of p62/SQSTM1 in promoting lipophagy by binding to ADRP on the LD .…”

Section: Discussionsupporting

confidence: 83%

Therapeutic targeting of PFKFB3 with a novel glycolytic inhibitor PFK158 promotes lipophagy and chemosensitivity in gynecologic cancers

Mondal

Roy

Bhattacharya

et al. 2018

Intl Journal of Cancer

110

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Metabolic alterations are increasingly recognized as important novel anti-cancer targets. Among several regulators of metabolic alterations, fructose 2,6 bisphosphate (F2,6BP) is a critical glycolytic regulator. Inhibition of the active form of PFKFB3 using a novel inhibitor, PFK158 resulted in reduced glucose uptake, ATP production, lactate release as well as induction of apoptosis in gynecologic cancer cells. Moreover, we found that PFK158 synergizes with carboplatin (CBPt) and paclitaxel (PTX) in the chemoresistant cell lines, C13 and HeyA8MDR but not in their chemosensitive counterparts, OV2008 and HeyA8, respectively. We determined that PFK158-induced autophagic flux leads to lipophagy resulting in the downregulation of cPLA2, a lipid droplet (LD) associated protein. Immunofluorescence and co-immunoprecipitation revealed colocalization of p62/SQSTM1 with cPLA2 in HeyA8MDR cells uncovering a novel pathway for the breakdown of LDs promoted by PFK158. Interestingly, treating the cells with the autophagic inhibitor bafilomycin A reversed the PFK158-mediated synergy and lipophagy in chemoresistant cells. Finally, in a highly metastatic PTX-resistant in vivo ovarian mouse model, a combination of PFK158 with CBPt significantly reduced tumor weight and ascites and reduced LDs in tumor tissue as seen by immunofluorescence and transmission electron microscopy compared to untreated mice. Since the majority of cancer patients will eventually recur and develop chemoresistance, our results suggest that PFK158 in combination with standard chemotherapy may have a direct clinical role in the treatment of recurrent cancer.

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Section: Discussionsupporting

confidence: 83%

Therapeutic targeting of PFKFB3 with a novel glycolytic inhibitor PFK158 promotes lipophagy and chemosensitivity in gynecologic cancers

Mondal

Roy

Bhattacharya

et al. 2018

Intl Journal of Cancer

110

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“…A recent study from our laboratory has explored if there is linearity in the relationship between ATGL and autophagy/lipophagy [17]. In this work, ATGL was shown to be both necessary and sufficient to promote the expression of autophagy genes in the liver.…”

Section: Proteins Involved In Lipophagy Inductionmentioning

confidence: 99%

Breaking fat: The regulation and mechanisms of lipophagy

Schulze

Sathyanarayan

Mashek

2017

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

Self Cite

176

115

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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.

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“…4b). Finally, ATGL was recently shown to markedly influence autophagy through SIRT1-dependent transcriptional regulation [47 ▪▪ ]. Particularly remarkable is that in hepatocytes, the increase in lipophagy driven by ATGL overexpression seemed to be far more relevant to fatty acid liberation than ATGL activity itself.…”

Section: Alternative Functions Of Autophagy Machinery In Lipid Metabomentioning

confidence: 99%

Classical and alternative roles for autophagy in lipid metabolism

Zhang

Evans

Jeong

et al. 2018

Current Opinion in Lipidology

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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.

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ATGL Promotes Autophagy/Lipophagy via SIRT1 to Control Hepatic Lipid Droplet Catabolism

Cited by 266 publications

References 39 publications

Therapeutic targeting of PFKFB3 with a novel glycolytic inhibitor PFK158 promotes lipophagy and chemosensitivity in gynecologic cancers

Therapeutic targeting of PFKFB3 with a novel glycolytic inhibitor PFK158 promotes lipophagy and chemosensitivity in gynecologic cancers

Breaking fat: The regulation and mechanisms of lipophagy

Classical and alternative roles for autophagy in lipid metabolism

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