Lipid Droplet-Associated Hydrolase Promotes Lipid Droplet Fusion and Enhances ATGL Degradation and Triglyceride Accumulation

Abstract Lipid droplet (LD)-associated hydrolase (LDAH) is a newly identified LD protein abundantly expressed in tissues that predominantly store triacylglycerol (TAG). However, how LDAH regulates TAG metabolism remains unknown. We found that upon oleic acid loading LDAH translocalizes from the ER t...

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Autores principales:	Young-Hwa Goo, Se-Hee Son, Antoni Paul
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/787be6507a3d46d9aa68b06ef232133f
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spelling	oai:doaj.org-article:787be6507a3d46d9aa68b06ef232133f2021-12-02T11:40:53ZLipid Droplet-Associated Hydrolase Promotes Lipid Droplet Fusion and Enhances ATGL Degradation and Triglyceride Accumulation10.1038/s41598-017-02963-y2045-2322https://doaj.org/article/787be6507a3d46d9aa68b06ef232133f2017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02963-yhttps://doaj.org/toc/2045-2322Abstract Lipid droplet (LD)-associated hydrolase (LDAH) is a newly identified LD protein abundantly expressed in tissues that predominantly store triacylglycerol (TAG). However, how LDAH regulates TAG metabolism remains unknown. We found that upon oleic acid loading LDAH translocalizes from the ER to newly formed LDs, and induces LD coalescence in a tubulin-dependent manner. LDAH overexpression and downregulation in HEK293 cells increase and decrease, respectively, TAG levels. Pulse and chase experiments show that LDAH enhances TAG biogenesis, but also decreases TAG turnover and fatty acid release from cells. Mutations in predicted catalytic and acyltransferase motifs do not influence TAG levels, suggesting that the effect is independent of LDAH’s enzymatic activity. However, a LDAH alternative-splicing variant missing 90 amino acids at C-terminus does not promote LD fusion or TAG accumulation, while it still localizes to LDs. Interestingly, LDAH enhances polyubiquitination and proteasomal degradation of adipose triglyceride lipase (ATGL), a rate limiting enzyme of TAG hydrolysis. Co-expression of ATGL reverses the changes in LD phenotype induced by LDAH, and both proteins counterbalance their effects on TAG stores. Together, these studies support that under conditions of TAG storage in LDs LDAH plays a primarily lipogenic role, inducing LD growth and enhancing degradation of ATGL.Young-Hwa GooSe-Hee SonAntoni PaulNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Young-Hwa Goo Se-Hee Son Antoni Paul Lipid Droplet-Associated Hydrolase Promotes Lipid Droplet Fusion and Enhances ATGL Degradation and Triglyceride Accumulation
description	Abstract Lipid droplet (LD)-associated hydrolase (LDAH) is a newly identified LD protein abundantly expressed in tissues that predominantly store triacylglycerol (TAG). However, how LDAH regulates TAG metabolism remains unknown. We found that upon oleic acid loading LDAH translocalizes from the ER to newly formed LDs, and induces LD coalescence in a tubulin-dependent manner. LDAH overexpression and downregulation in HEK293 cells increase and decrease, respectively, TAG levels. Pulse and chase experiments show that LDAH enhances TAG biogenesis, but also decreases TAG turnover and fatty acid release from cells. Mutations in predicted catalytic and acyltransferase motifs do not influence TAG levels, suggesting that the effect is independent of LDAH’s enzymatic activity. However, a LDAH alternative-splicing variant missing 90 amino acids at C-terminus does not promote LD fusion or TAG accumulation, while it still localizes to LDs. Interestingly, LDAH enhances polyubiquitination and proteasomal degradation of adipose triglyceride lipase (ATGL), a rate limiting enzyme of TAG hydrolysis. Co-expression of ATGL reverses the changes in LD phenotype induced by LDAH, and both proteins counterbalance their effects on TAG stores. Together, these studies support that under conditions of TAG storage in LDs LDAH plays a primarily lipogenic role, inducing LD growth and enhancing degradation of ATGL.
format	article
author	Young-Hwa Goo Se-Hee Son Antoni Paul
author_facet	Young-Hwa Goo Se-Hee Son Antoni Paul
author_sort	Young-Hwa Goo
title	Lipid Droplet-Associated Hydrolase Promotes Lipid Droplet Fusion and Enhances ATGL Degradation and Triglyceride Accumulation
title_short	Lipid Droplet-Associated Hydrolase Promotes Lipid Droplet Fusion and Enhances ATGL Degradation and Triglyceride Accumulation
title_full	Lipid Droplet-Associated Hydrolase Promotes Lipid Droplet Fusion and Enhances ATGL Degradation and Triglyceride Accumulation
title_fullStr	Lipid Droplet-Associated Hydrolase Promotes Lipid Droplet Fusion and Enhances ATGL Degradation and Triglyceride Accumulation
title_full_unstemmed	Lipid Droplet-Associated Hydrolase Promotes Lipid Droplet Fusion and Enhances ATGL Degradation and Triglyceride Accumulation
title_sort	lipid droplet-associated hydrolase promotes lipid droplet fusion and enhances atgl degradation and triglyceride accumulation
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/787be6507a3d46d9aa68b06ef232133f
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Lipid Droplet-Associated Hydrolase Promotes Lipid Droplet Fusion and Enhances ATGL Degradation and Triglyceride Accumulation

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