Lipid droplet meets a mitochondrial protein to regulate adipocyte lipolysis

Greenberg, Andrew S.; Kraemer, Fredric B.; Soni, Krishnakant G.; Jedrychowski, Mark P.; Yan, Qing-Wu; Graham, Christine; Bowman, Thomas A.; Mansur, Ayla

doi:10.1038/emboj.2011.371

Cited by 18 publications

(13 citation statements)

References 10 publications

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“…OPA1, the A-kinase anchoring protein (AKAP), interacts with Plin1 on LD and tethers PKA subunits (Greenberg et al 2011;Pidoux et al 2011). Effects of isoproterenol (IS) stimulation on Neu1 and Plin1 interactions and of Neu1 knockdown on interactions between Plin1 and HSL induced by IS in 3T3-L1 adipocytes.…”

Section: Discussionmentioning

confidence: 99%

“…However, these complexes do not form in the Cav1 null mouse and Plin1 phosphorylation by PKA and lipolytic activity is attenuated in WAT from this mouse . OPA1, the A-kinase anchoring protein (AKAP), interacts with Plin1 on LD and tethers PKA subunits (Greenberg et al 2011;Pidoux et al 2011). Introducing mutated OPA1, which is the unbound form of PKA subunits, into adipocytes inhibits Plin1 phosphorylation without altering HSL phosphorylation upon b-adrenergic stimulation (Greenberg et al 2011;Pidoux et al 2011).…”

Section: Discussionmentioning

confidence: 99%

“…OPA1, the A-kinase anchoring protein (AKAP), interacts with Plin1 on LD and tethers PKA subunits (Greenberg et al 2011;Pidoux et al 2011). Introducing mutated OPA1, which is the unbound form of PKA subunits, into adipocytes inhibits Plin1 phosphorylation without altering HSL phosphorylation upon b-adrenergic stimulation (Greenberg et al 2011;Pidoux et al 2011). In the present study, we showed that Neu1 knockdown increased Plin1 phosphorylation without altering HSL phosphorylation after IS stimulation.…”

Section: Discussionmentioning

confidence: 99%

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Neu1 sialidase interacts with perilipin 1 on lipid droplets and inhibits lipolysis in 3T3‐L1 adipocytes

2017

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Fatty acids are stored within adipocytes in lipid droplets (LDs) as triacylglycerol (TG), which is converted to free fatty acid (FFA) and glycerol via lipolysis. Increased plasma FFA levels in obesity are associated with several clinical conditions. We previously found that Neu1 activity is aberrant in the epididymal fat and liver of obese and diabetic mice. Here, we examined involvement of Neu1 in lipolysis in 3T3-L1 adipocytes. Small interfering RNA against Neu1 was introduced into adipocytes, and glycerol concentrations were measured in the culture medium. We then assessed the effects of Neu1 knockdown on lipolytic protein expression and phosphorylation, as well as interactions between perilipin 1 (Plin1) and hormone-sensitive lipase (HSL) after isoproterenol (IS) stimulation. Interactions between Neu1 and Plin1 were analyzed by immunoprecipitation and immunofluorescent imaging using adipocytes transfected with pCMV6-mNeu1-myc-DYKDDDDK (mNeu1DDK). Neu1 knockdown increased glycerol concentrations in culture media and Plin1 phosphorylation in whole lysates of IS-stimulated cells. Neu1 knockdown increased interaction between Plin1 and HSL after IS stimulation whereas that between Neu1 and Plin1 on LD observed under basal conditions was lost. These results suggest that Neu1 inhibits lipolysis induced by β-adrenergic stimulation in adipocytes via interactions with Plin1 on LD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Neu1 sialidase interacts with perilipin 1 on lipid droplets and inhibits lipolysis in 3T3‐L1 adipocytes

2017

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“…Under stress situations such as obesity or alcohol-induced damage, hepatocytes accumulate fat in lipid droplets (LDs), which contributes to the development of hepatosteatosis (Gluchowski, Becuwe, Walther and Farese, 2017). LDs are dynamic metabolic stations (Greenberg, Kraemer, Soni, Jedrychowski, Yan, Graham, Bowman and Mansur, 2011), formed by a core of neutral lipids surrounded by a phospholipid membrane and proteins, of which members of the perilipin (Plin) family are amongst the most important. Perilipins are a family of proteins that coat LDs, controlling their biogenesis, stabilization, and preventing their degradation.…”

Section: Introductionmentioning

confidence: 99%

mTORC1-Plin3 pathway is essential to activate lipophagy and protects against hepatosteatosis

García-Macia

Santos-Ledo

Leslie

et al. 2019

Preprint

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During postprandial state, the liver is exposed to high levels of dietary fatty acids (FAs) and carbohydrates. FAs are re-esterified into triglycerides, which can be stored in lipid droplets (LDs) in the liver. Aberrant accumulation of LDs can lead to diseases such as alcoholic liver disease and non-alcoholic fatty liver disease, the latter being the most common liver pathology in western countries. Improved understanding of LD biology has potential to unlock new treatments for these liver diseases. The Perilipin (Plin) family is the group of proteins that coat LDs, controlling their biogenesis, stabilization, and preventing their degradation. Recent studies have revealed that autophagy is involved in LD degradation and, therefore, may be crucial to avoid lipid accumulation. Here, we show that a phosphorylated form of Plin3 is required for selective degradation of LDs in fibroblasts, primary hepatocytes and human liver slices. We demonstrate that oleic acid treatment induces the recruitment of the autophagy machinery to the surface of LDs. When Plin3 is silenced, this recruitment is suppressed resulting in accumulation of lipid. Plin3 pulldowns revealed interactions with the autophagy initiator proteins Fip200 and Atg16L indicating that Plin3 may function as a docking protein involved in lipophagy activation. Of particular importance, we define Plin3 as a substrate for mTORC1-dependent phosphorylation and show that this event is decisive for lipophagy. Our study therefore reveals that Plin3, and its phosphorylation by mTORC1, is crucial for degradation of LDs by autophagy. We propose that stimulating this pathway to enhance LD autophagy in hepatocytes will help protect the liver from lipid-mediated toxicity thus offering new therapeutic opportunities in human steatotic liver diseases.

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“…Recently, the crystal structure of a photolyase (PHRs)-DNA lesion complex has been solved by X-ray measurement [ 18 – 20 ]. In this structure, the DNA lesion deviates from the double strand DNA and interacts with a binding pocket in the PHRs (see Fig.…”

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confidence: 99%

Theoretical analyses on a flipping mechanism of UV-induced DNA damage

2016

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As for UV-induced DNA damage, which may induce skin cancer in animals and growth inhibition in plants, there are two types of photoproducts, namely cis-sin cyclobutane pyrimidine dimers (CPD) and pyrimidine-pyrimidone (6-4) photoproducts. When they are to be repaired, base-flipping occurs, and they bind to enzymes. However, this process remains relatively unknown at a molecular level. We analyze conformation and interaction energy changes upon base-flipping using classical molecular dynamics (CMD) simulations and ab initio electronic structure calculations. CMD simulations starting with a CPD in the flipped-in and flipped-out states showed that both states were unchanged for 500 ns, indicating the flipped-in and flipped-out processes do not occur spontaneously (without any help of the enzyme) after photo-damage. To deeply understand the reasons, we investigated interaction energy changes among bases upon structure changes during the flipped-in and flipped-out processes using Parallel Cascade Selection-MD (PaCS-MD) simulations at 400 K, followed by a fragment molecular orbital (FMO) method. The total inter-fragment interaction energy (IFIE) between CPD and other bases at the flipped-in state is estimated to be −60.08 kcal/mol. In particular, four bases strongly interact with CPD with interaction energies being −10.96, −13.70, −21.52, and −14.46 kcal/mol each. On the other hand, the total IFIE at the obtained flipped-out state increased to −10.40 kcal/mol by partly losing hydrogen bonds and π-π stacking interactions, respectively. These results clearly indicate that the base-flipping process of DNA lesions occurs with the help of external forces like interactions with appropriate enzymes such as photolyases.

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Lipid droplet meets a mitochondrial protein to regulate adipocyte lipolysis

Abstract: Optic Atrophy 1 (OPA1) is well known as a regulator of mitochondrial dynamics. Now, a new function of OPA1 is uncovered: recruiting protein kinase A to lipid droplets, thereby controlling the activity of perilipin, and hence lipolysis.

Cited by 18 publications

References 10 publications

Neu1 sialidase interacts with perilipin 1 on lipid droplets and inhibits lipolysis in 3T3‐L1 adipocytes

Neu1 sialidase interacts with perilipin 1 on lipid droplets and inhibits lipolysis in 3T3‐L1 adipocytes

mTORC1-Plin3 pathway is essential to activate lipophagy and protects against hepatosteatosis

Theoretical analyses on a flipping mechanism of UV-induced DNA damage

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