scholarly journals Rab18 promotes lipid droplet (LD) growth by tethering the ER to LDs through SNARE and NRZ interactions

2018 ◽  
Vol 217 (3) ◽  
pp. 975-995 ◽  
Author(s):  
Dijin Xu ◽  
Yuqi Li ◽  
Lizhen Wu ◽  
Ying Li ◽  
Dongyu Zhao ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Lipid Droplet ◽  
Cross Talk ◽  
Complex Function ◽  
Lipid Storage ◽  
Snare Complex ◽  
Lipid Homeostasis ◽  
Intracellular Lipid ◽  
Guanosine Triphosphatase

Lipid incorporation from endoplasmic reticulum (ER) to lipid droplet (LD) is important in controlling LD growth and intracellular lipid homeostasis. However, the molecular link mediating ER and LD cross talk remains elusive. Here, we identified Rab18 as an important Rab guanosine triphosphatase in controlling LD growth and maturation. Rab18 deficiency resulted in a drastically reduced number of mature LDs and decreased lipid storage, and was accompanied by increased ER stress. Rab3GAP1/2, the GEF of Rab18, promoted LD growth by activating and targeting Rab18 to LDs. LD-associated Rab18 bound specifically to the ER-associated NAG-RINT1-ZW10 (NRZ) tethering complex and their associated SNAREs (Syntaxin18, Use1, BNIP1), resulting in the recruitment of ER to LD and the formation of direct ER–LD contact. Cells with defects in the NRZ/SNARE complex function showed reduced LD growth and lipid storage. Overall, our data reveal that the Rab18-NRZ-SNARE complex is critical protein machinery for tethering ER–LD and establishing ER–LD contact to promote LD growth.

scholarly journals Lipid perturbation-activated IRE-1 modulates autophagy and lipolysis during endoplasmic reticulum stress

2018 ◽  
Author(s):  
Jhee Hong Koh ◽  
Lei Wang ◽  
Caroline Beaudoin-Chabot ◽  
Guillaume Thibault
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Lipid Droplet ◽  
Metabolic Diseases ◽  
Phospholipid Composition ◽  
Emerging Diseases ◽  
Lipid Homeostasis ◽  
Dependent Manner ◽  
Proteotoxic Stress

ABSTRACTMetabolic disorders such as obesity and nonalcoholic fatty liver disease (NAFLD) are emerging diseases that affect the global population. One facet of these disorders is attributed to the disturbance of membrane lipid composition. Perturbation of endoplasmic reticulum (ER) homeostasis through changes in membrane phospholipid composition results in activation of the unfolded protein response (UPR) and causes dramatic translational and transcriptional changes in the cell. To restore cellular homeostasis, the three highly conserved UPR transducers ATF6, IRE1, and PERK mediate cellular processes upon ER stress. The role of the UPR in proteotoxic stress caused by the accumulation of misfolded proteins is well understood but much less so under lipid perturbation-induced UPR (UPRLP). We found that genetically disrupted phosphatidylcholine synthesis in C. elegans causes, lipid perturbation, lipid droplet accumulation, and induced ER stress, all hallmarks of NAFLD. Transcriptional profiling of UPRLP animals shows a unique subset of genes modulated in an UPR-dependent manner that is unaffected by proteotoxic stress (UPRPT). Among these, we identified autophagy genes bec-1 and lgg-1 and the lipid droplet-associated lipase atgl-1 to be modulated by IRE-1. Considering the important role of lipid homeostasis and how its impairment contributes to the pathology of metabolic diseases, our data uncovers the indispensable role of a fully functional UPR program in regulating lipid homeostasis in the face of chronic ER stress and lipotoxicity.

scholarly journals SEIPIN: A Key Factor for Nuclear Lipid Droplet Generation and Lipid Homeostasis

2020 ◽  
Vol 21 (21) ◽  
pp. 8208
Author(s):  
Yi Jin ◽  
Yanjie Tan ◽  
Pengxiang Zhao ◽  
Zhuqing Ren
Keyword(s):  
Endoplasmic Reticulum ◽  
Lipid Droplet ◽  
Normal Cell ◽  
Single Layer ◽  
Lipid Homeostasis ◽  
Cell Physiology ◽  
Phospholipid Membrane ◽  
Key Factor

Lipid homeostasis is essential for normal cell physiology. Generally, lipids are stored in a lipid droplet (LD), a ubiquitous organelle consisting of a neutral lipid core and a single layer of phospholipid membrane. It is thought that LDs are generated from the endoplasmic reticulum and then released into the cytosol. Recent studies indicate that LDs can exist in the nucleus, where they play an important role in the maintenance of cell phospholipid homeostasis. However, the details of nuclear lipid droplet (nLD) generation have not yet been clearly characterized. SEIPIN is a nonenzymatic protein encoded by the Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) gene. It is associated with lipodystrophy diseases. Many recent studies have indicated that SEIPIN is essential for LDs generation. Here, we review much of this research in an attempt to explain the role of SEIPIN in nLD generation. From an integrative perspective, we conclude by proposing a theoretical model to explain how SEIPIN might participate in maintaining homeostasis of lipid metabolism.

scholarly journals Endoplasmic Reticulum Stress Disturbs Lipid Homeostasis and Augments Inflammation in the Intestine and Isolated Intestinal Cells of Large Yellow Croaker (Larimichthys crocea)

2021 ◽  
Vol 12 ◽  
Author(s):  
Wei Fang ◽  
Qiuchi Chen ◽  
Jiamin Li ◽  
Yongtao Liu ◽  
Zengqi Zhao ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Lipid Metabolism ◽  
Er Stress ◽  
Lipid Synthesis ◽  
Whole Body ◽  
Lipid Homeostasis ◽  
Intestinal Cells ◽  
Large Yellow Croaker ◽  
Human Beings ◽  
Larimichthys Crocea

The small intestine is crucial for lipid homeostasis and immune regulation of the whole body. Endoplasmic reticulum (ER) stress may affect lipid metabolism and inflammation in the intestine, but the potential mechanism is not completely understood. In the present study, intraperitoneal injection of tunicamycin (TM) induced ER stress in the intestine of large yellow croaker (Larimichthys crocea). ER stress induced excessive accumulation of triglyceride (TG) in the intestine by promoting lipid synthesis. However, it also enhanced lipid secretion and fatty acid β-oxidation. In addition, ER stress augmented inflammation in the intestine by promoting p65 into the nucleus and increasing proinflammatory genes expression. In the isolated intestinal cells, the obtained results showed that TM treatment significantly upregulated the mRNA expression of lipid synthesis and inflammatory response genes, which were consistent with those in vivo. Moreover, overexpression of unfolded protein response (UPR) sensors significantly upregulated promoter activities of lipid synthesis and proinflammatory genes. In conclusion, the results suggested that ER stress disturbed lipid metabolism and augmented inflammation in the intestine and isolated intestinal cells of large yellow croaker, which may contribute to finding novel therapies to tackle lipid dysregulation and inflammation in the intestine of fish and human beings.

scholarly journals Acyl-CoA synthetase 3 promotes lipid droplet biogenesis in ER microdomains

2013 ◽  
Vol 203 (6) ◽  
pp. 985-1001 ◽  
Author(s):  
Adam Kassan ◽  
Albert Herms ◽  
Andrea Fernández-Vidal ◽  
Marta Bosch ◽  
Nicole L. Schieber ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Endoplasmic Reticulum ◽  
Lipid Droplet ◽  
Copy Number ◽  
Storage Capacity ◽  
Neutral Lipids ◽  
Electron Tomography ◽  
Lipid Storage ◽  
Lipid Concentration ◽  
Stable Core

Control of lipid droplet (LD) nucleation and copy number are critical, yet poorly understood, processes. We use model peptides that shift from the endoplasmic reticulum (ER) to LDs in response to fatty acids to characterize the initial steps of LD formation occurring in lipid-starved cells. Initially, arriving lipids are rapidly packed in LDs that are resistant to starvation (pre-LDs). Pre-LDs are restricted ER microdomains with a stable core of neutral lipids. Subsequently, a first round of “emerging” LDs is nucleated, providing additional lipid storage capacity. Finally, in proportion to lipid concentration, new rounds of LDs progressively assemble. Confocal microscopy and electron tomography suggest that emerging LDs are nucleated in a limited number of ER microdomains after a synchronized stepwise process of protein gathering, lipid packaging, and recognition by Plin3 and Plin2. A comparative analysis demonstrates that the acyl-CoA synthetase 3 is recruited early to the assembly sites, where it is required for efficient LD nucleation and lipid storage.

scholarly journals Induction of Liver Steatosis and Lipid Droplet Formation in ATF6α-Knockout Mice Burdened with Pharmacological Endoplasmic Reticulum Stress

2010 ◽  
Vol 21 (17) ◽  
pp. 2975-2986 ◽  
Author(s):  
Keisuke Yamamoto ◽  
Kazuna Takahara ◽  
Seiichi Oyadomari ◽  
Tetsuya Okada ◽  
Takashi Sato ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Lipid Droplet ◽  
Knockout Mice ◽  
Neutral Lipids ◽  
Liver Steatosis ◽  
Droplet Formation ◽  
Mrna Levels ◽  
Lipid Droplet Formation ◽  
Transcriptional Induction

Accumulation of unfolded proteins in the endoplasmic reticulum (ER) activates homeostatic responses collectively termed the unfolded protein response. Among the three principal signaling pathways operating in mammals, activating transcription factor (ATF)6α plays a pivotal role in transcriptional induction of ER-localized molecular chaperones and folding enzymes as well as components of ER-associated degradation, and thereby mouse embryonic fibroblasts deficient in ATF6α are sensitive to ER stress. However, ATF6α-knockout mice show no apparent phenotype under normal growing conditions. In this report, we burdened mice with intraperitoneal injection of the ER stress-inducing reagent tunicamycin and found that wild-type mice were able to recover from the insult, whereas ATF6α-knockout mice exhibited liver dysfunction and steatosis. Thus, ATF6α-knockout mice accumulated neutral lipids in the liver such as triacylglycerol and cholesterol, which was ascribable to blockage of β-oxidation of fatty acids caused by decreased mRNA levels of the enzymes involved in the process, suppression of very-low-density lipoprotein formation due to destabilized apolipoprotein B-100, and stimulation of lipid droplet formation resulting from transcriptional induction of adipose differentiation-related protein. Accordingly, the hepatocytes of tunicamycin-injected knockout mice were filled with many lipid droplets. These results establish links among ER stress, lipid metabolism, and steatosis.

scholarly journals Cross-talk between Endoplasmic Reticulum (ER) Stress and the MEK/ERK Pathway Potentiates Apoptosis in Human Triple Negative Breast Carcinoma Cells

2014 ◽  
Vol 290 (7) ◽  
pp. 3936-3949 ◽  
Author(s):  
Swatilekha Ghosh ◽  
Arghya Adhikary ◽  
Supriya Chakraborty ◽  
Pushpak Bhattacharjee ◽  
Minakshi Mazumder ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Breast Carcinoma ◽  
Er Stress ◽  
Cross Talk ◽  
Triple Negative ◽  
Carcinoma Cells ◽  
Erk Pathway ◽  
Breast Carcinoma Cells ◽  
Triple Negative Breast Carcinoma

An endoplasmic reticulum-targeting fluorescent probe for imaging ˙OH in living cells

2020 ◽  
Vol 56 (47) ◽  
pp. 6344-6347 ◽  
Author(s):  
Yanyan Zhao ◽  
Hongyu Li ◽  
Ziyin Chai ◽  
Wen Shi ◽  
Xiaohua Li ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Fluorescent Probe ◽  
Lipid Droplet ◽  
Droplet Formation ◽  
Living Cells ◽  
Lipid Droplet Formation ◽  
Er Targeting ◽  
Endoplasmic Reticulum Targeting

A new ER-targeting fluorescent probe for ˙OH is developed and applied to imaging ˙OH generation as well as lipid droplet formation in ER stress.

scholarly journals The Stress of Lung Aging: Endoplasmic Reticulum and Senescence Tête-à-Tête

Physiology ◽  
2021 ◽  
Vol 36 (3) ◽  
pp. 150-159 ◽  
Author(s):  
M. L. Koloko Ngassie ◽  
C. A. Brandsma ◽  
R. Gosens ◽  
Y. S. Prakash ◽  
J. K. Burgess
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Er Stress ◽  
Cigarette Smoke ◽  
Cross Talk ◽  
Structural Changes ◽  
Er Stress Response ◽  
Lung Aging

Beyond the structural changes, features including the dysregulation of endoplasmic reticulum (ER) stress response and increased senescence characterize the lung aging. ER stress response and senescence have been reported to be induced by factors like cigarette smoke. Therefore, deciphering the mechanisms underlying ER and senescent pathways interaction has become a challenge. In this review we highlight the known and unknown regarding ER stress response and senescence and their cross talk in aged lung.

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