Characterization of the interaction of diacylglycerol acyltransferase-2 with the endoplasmic reticulum and lipid droplets

McFie, Pamela J.; Jin, Youzhi; Banman, Shanna L.; Beauchamp, Erwan; Berthiaume, Luc G.; Stone, Scot J.

doi:10.1016/j.bbalip.2014.06.004

Cited by 16 publications

(14 citation statements)

References 45 publications

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“…Therefore, we hypothesized that acylceramide generation can take place at the ER/LD interface and tested the presence of CerS in the LD. Consistent with previous reports (Harris et al, 2011; McFie et al, 2014), confocal microscopy revealed that transiently expressed ACSL5 and DGAT2 co-localized with calnexin at the ER (Figure 6C) and on the ER/LD interface upon oleate loading (Figure 6D). Similar to ACSL5, CerS6 and DGAT2 co-localized on ER membranes in control cells (Figure 6E) and on the LD membranes upon oleate loading as detected by microscopy (Figure 6F) and cellular fractionation (Figures 6G and S6A).…”

Section: Resultssupporting

confidence: 92%

Ceramide Is Metabolized to Acylceramide and Stored in Lipid Droplets

et al. 2017

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SUMMARY In an approach aimed at defining interacting partners of ceramide synthases (CerS), we found that fatty acyl CoA synthase ACSL5 interacts with all CerS. We demonstrate that ACSL5 generated FA-CoA was utilized with de novo ceramide for the generation of acylceramides, poorly studied ceramide metabolites. Functionally, inhibition of ceramide channeling to acylceramide enhanced accumulation of de novo ceramide and resulted in augmentation of ceramide-mediated apoptosis. Mechanistically, we show that acylceramide generation is catalyzed by diacylglycerol acyltransferase 2 (DGAT2) on lipid droplets. In summary, this study identifies a metabolic pathway of acylceramide generation and its sequestration in LD in cells and in livers of mice on a high fat diet. The study also implicates this novel pathway in ceramide-mediated apoptosis, and has implications in co-regulation of triglyceride and sphingolipid metabolisms.

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Section: Resultssupporting

confidence: 92%

Ceramide Is Metabolized to Acylceramide and Stored in Lipid Droplets

et al. 2017

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“…DGAT1 is a member of the acyl-CoA:cholesterol acyltransferase family and is an ER-restricted polytopic membrane protein (203). In contrast, DGAT2 is a member of the monoacylglycerol acyltransferase family and has a hairpin topology (109, 171, 203). DGAT2 contains two transmembrane domains joined by a small number of amino acids that are potentially in the ER lumen, and the amino and carboxyl termini are oriented toward the cytosol (109, 171).…”

Section: Erad Regulation Of Triacylglycerol Metabolismmentioning

confidence: 99%

“…In contrast, DGAT2 is a member of the monoacylglycerol acyltransferase family and has a hairpin topology (109, 171, 203). DGAT2 contains two transmembrane domains joined by a small number of amino acids that are potentially in the ER lumen, and the amino and carboxyl termini are oriented toward the cytosol (109, 171). This hairpin conformation is necessary, but not sufficient, for DGAT2 trafficking from the ER to LDs in response to FA (109, 171).…”

Section: Erad Regulation Of Triacylglycerol Metabolismmentioning

confidence: 99%

“…DGAT2 contains two transmembrane domains joined by a small number of amino acids that are potentially in the ER lumen, and the amino and carboxyl termini are oriented toward the cytosol (109, 171). This hairpin conformation is necessary, but not sufficient, for DGAT2 trafficking from the ER to LDs in response to FA (109, 171). On LDs, DGAT2 cooperates with other TAG synthesis enzymes and contributes to local TAG synthesis and LD growth (194).…”

Section: Erad Regulation Of Triacylglycerol Metabolismmentioning

confidence: 99%

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Endoplasmic Reticulum–Associated Degradation and Lipid Homeostasis

2016

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The endoplasmic reticulum is the port of entry for proteins into the secretory pathway and the site of synthesis for several important lipids, including cholesterol, triacylglycerol, and phospholipids. Protein production within the endoplasmic reticulum is tightly regulated by a cohort of resident machinery that coordinates the folding, modification, and deployment of secreted and integral membrane proteins. Proteins failing to attain their native conformation are degraded through the endoplasmic reticulum–associated degradation (ERAD) pathway via a series of tightly coupled steps: substrate recognition, dislocation, and ubiquitin-dependent proteasomal destruction. The same ERAD machinery also controls the flux through various metabolic pathways by coupling the turnover of metabolic enzymes to the levels of key metabolites. We review the current understanding and biological significance of ERAD-mediated regulation of lipid metabolism in mammalian cells.

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“…The isoforms possess different structural features and only show partially redundant functions (Liu et al, 2012). DGAT1 is an integral membrane protein of the ER (McFie et al, 2010), whereas membrane association of DGAT2 is likely to be caused by a hairpin structure that mediates only a partial insertion into the membrane (McFie et al, 2014;Stone et al, 2006). These different modes of membrane localization could both result in hydrophobic mismatches and membrane curvature, which can give rise to local defects that are favorable for TAG accumulation (Fig.…”

Section: Lipid Droplet Emergencementioning

confidence: 99%

The why, when and how of lipid droplet diversity

Thiam

Beller

2017

Journal of Cell Science

234

180

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Lipid droplets are the universal cellular organelles for the transient or long-term storage of lipids. The number, size and composition of lipid droplets vary greatly within cells in a homogenous population as well as in different cell types. The variability of intracellular lipidstorage organelles reflects the diversification of lipid droplet composition and function. Lipid droplet diversification results, for example, in two cellular lipid droplet populations that are prone to diminish and grow, respectively. The aberrant accumulation or depletion of lipids are hallmarks or causes of various human pathologies. Thus, a better understanding of the origins of lipid droplet diversification is not only a fascinating cell biology question but also potentially serves to improve comprehension of pathologies that entail the accumulation of lipids. This Commentary covers the lipid droplet life cycle and highlights the early steps during lipid droplet biogenesis, which we propose to be the potential driving forces of lipid droplet diversification.

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Characterization of the interaction of diacylglycerol acyltransferase-2 with the endoplasmic reticulum and lipid droplets

Cited by 16 publications

References 45 publications

Ceramide Is Metabolized to Acylceramide and Stored in Lipid Droplets

Ceramide Is Metabolized to Acylceramide and Stored in Lipid Droplets

Endoplasmic Reticulum–Associated Degradation and Lipid Homeostasis

The why, when and how of lipid droplet diversity

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