scholarly journals STARD4 abundance regulates sterol transport and sensing

2011 ◽  
Vol 22 (21) ◽  
pp. 4004-4015 ◽  
Author(s):  
Bruno Mesmin ◽  
Nina H. Pipalia ◽  
Frederik W. Lund ◽  
Trudy F. Ramlall ◽  
Anna Sokolov ◽  
...  
Keyword(s):  
Cholesterol Homeostasis ◽  
Cholesterol Transport ◽  
Transcriptional Level ◽  
Lipid Transfer ◽  
Sterol Transport ◽  
Cholesterol Levels ◽  
Regulatory Machinery ◽  
Ester Formation ◽  
Steroidogenic Acute Regulatory

Nonvesicular transport of cholesterol plays an essential role in the distribution and regulation of cholesterol within cells, but it has been difficult to identify the key intracellular cholesterol transporters. The steroidogenic acute regulatory-related lipid-transfer (START) family of proteins is involved in several pathways of nonvesicular trafficking of sterols. Among them, STARD4 has been shown to increase intracellular cholesteryl ester formation and is controlled at the transcriptional level by sterol levels in cells. We found that STARD4 is very efficient in transporting sterol between membranes in vitro. Cholesterol levels are increased in STARD4-silenced cells, while sterol transport to the endocytic recycling compartment (ERC) and to the endoplasmic reticulum (ER) are enhanced upon STARD4 overexpression. STARD4 silencing attenuates cholesterol-mediated regulation of SREBP-2 activation, while its overexpression amplifies sterol sensing by SCAP/SREBP-2. To analyze STARD4's mode of action, we compared sterol transport mediated by STARD4 with that of a simple sterol carrier, methyl-β-cyclodextrin (MCD), when STARD4 and MCD were overexpressed or injected into cells. Interestingly, STARD4 and cytosolic MCD act similarly by increasing the rate of transfer of sterol to the ERC and to the ER. Our results suggest that cholesterol transport mediated by STARD4 is an important component of the cholesterol homeostasis regulatory machinery.

Stard 3 (Steroidogenic Acute Regulatory-Related Lipid Transfer Domain-Containing Protein 3) Play Important Role in Preadipocyte Differentiation

2022 ◽  
Vol 12 (4) ◽  
pp. 827-833
Author(s):  
Zhonge Chen ◽  
Yanhua Tang ◽  
Wenyong Jiang ◽  
Xiaoqian Zhou
Keyword(s):  
Fluorescence Intensity ◽  
Lipid Transfer ◽  
Gene Expressions ◽  
Preadipocyte Differentiation ◽  
Protein Expressions ◽  
Positive Rate ◽  
Steroidogenic Acute Regulatory ◽  
Oil Red O Staining ◽  
Oil Red O

Aim: To evaluate Stard 3’s effects and relative mechanisms in preadipocyto differentiation by vitro study. Materials and Methods: The 3T3-L1 cell were divided into 5 groups as NC, si-Stard 3, ROS agonist, ROS inhibitor and si-Stard 3+ROS agonist groups. The cell of different groups were evaluated by Oil red O staining and Triglyceride. Evaluating ROS production by DHE and NBT assay. Using RT-qPCR and WB methods to evaluate gene and protein expressions. Results: Compared with NC group, Triglyceride, DHE fluorescence intensity and NBT positive rate were significantly down-regulation in si-Stard 3 and ROS inhibitor groups (P < 0.001, respectively), and were significantly up-regulation in ROS agonist group (P < 0.001, respectively); However, with si-Stard 3 transfection and ROS agonist treatment, compared with si-Stard 3 group, Triglyceride, DHE fluorescence intensity and NBT positive rate were significantly increased in si-Stard 3+ROS agonist group (P < 0.001, respectively). With RT-qPCR and WB assay, Compared with NC group, Stard 3 gene and protein expressions of si-Stard 3 and si-Stard 3+ROS agonist group were significantly depressed (P < 0.001, respectively), AMPK, PPARγ, CEBPα and FABP4 gene expressions were significantly differences in si-Stard 3, ROS agonist and ROS inhibitor groups (P < 0.001, respectively) and p-AMPK, PPARγ, CEBPα and FABP4 protein expressions were significantly differences in si-Stard 3, ROS agonist and ROS inhibitor groups (P < 0.001, respectively), with si-Stard 3 transfection and ROS agonist the relative gene and protein expressions were significantly resumed compared with si-Stard 3 group (P < 0.001, respectively). Conclusion: Stard 3 knockdown had effects to suppress 3T3-L1 cells transformation into adipocytes in vitro study.

scholarly journals ORP1L, ORP1S, and ORP2: Lipid Sensors and Transporters

Contact ◽  
2020 ◽  
Vol 3 ◽  
pp. 251525642095681
Author(s):  
Yvette C. Aw ◽  
Andrew J. Brown ◽  
Jia-Wei Wu ◽  
Hongyuan Yang
Keyword(s):  
Plasma Membrane ◽  
Cholesterol Homeostasis ◽  
Cholesterol Transport ◽  
Lipid Transfer ◽  
Cholesterol Trafficking ◽  
Lipid Transfer Proteins ◽  
Oxysterol Binding Protein ◽  
Membrane Contact ◽  
Related Proteins ◽  
Lipid Sensors

Lipid transfer proteins are crucial for intracellular cholesterol trafficking at sites of membrane contact. In the OSBP/ORPs (oxysterol binding protein and OSBP-related proteins) family of lipid transfer proteins, ORP1L, ORP1S and ORP2 play important roles in cholesterol transport. ORP1L is an endosome/lysosome-anchored cholesterol sensor which may also move cholesterol bidirectionally at the interface between the endoplasmic reticulum and the endosome/lysosome. ORP2 delivers cholesterol to the plasma membrane, driven by PI(4,5)P2 hydrolysis. ORP1S may also transport cholesterol to the plasma membrane, although it is unclear if phosphoinositides are involved. The source of cholesterol delivered to the plasma membrane by ORP1S and ORP2 remains unclear. This review summarises the roles of these proteins in maintaining cellular cholesterol homeostasis and in human disease.

scholarly journals StarD5: an ER stress protein regulates plasma membrane and intracellular cholesterol homeostasis

2019 ◽  
Vol 60 (6) ◽  
pp. 1087-1098 ◽  
Author(s):  
Daniel Rodriguez-Agudo ◽  
Leonel Malacrida ◽  
Genta Kakiyama ◽  
Tavis Sparrer ◽  
Carolina Fortes ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Er Stress ◽  
Stress Protein ◽  
Cholesterol Content ◽  
Cholesterol Homeostasis ◽  
Fluorescence Lifetime Imaging ◽  
Lipid Transfer ◽  
Altered Expression ◽  
Intracellular Cholesterol

How plasma membrane (PM) cholesterol is controlled is poorly understood. Ablation of the gene encoding the ER stress steroidogenic acute regulatory-related lipid transfer domain (StarD)5 leads to a decrease in PM cholesterol content, a decrease in cholesterol efflux, and an increase in intracellular neutral lipid accumulation in macrophages, the major cell type that expresses StarD5. ER stress increases StarD5 expression in mouse hepatocytes, which results in an increase in accessible PM cholesterol in WT but not in StarD5−/− hepatocytes. StarD5−/− mice store higher levels of cholesterol and triglycerides, which leads to altered expression of cholesterol-regulated genes. In vitro, a recombinant GST-StarD5 protein transfers cholesterol between synthetic liposomes. StarD5 overexpression leads to a marked increase in PM cholesterol. Phasor analysis of 6-dodecanoyl-2-dimethylaminonaphthalene fluorescence lifetime imaging microscopy data revealed an increase in PM fluidity in StarD5−/− macrophages. Taken together, these studies show that StarD5 is a stress-responsive protein that regulates PM cholesterol and intracellular cholesterol homeostasis.

scholarly journals STARD3: A Swiss Army Knife for Intracellular Cholesterol Transport

Contact ◽  
2019 ◽  
Vol 2 ◽  
pp. 251525641985673
Author(s):  
Laetitia Voilquin ◽  
Massimo Lodi ◽  
Thomas Di Mattia ◽  
Marie-Pierre Chenard ◽  
Carole Mathelin ◽  
...  
Keyword(s):  
Lipid Transfer Protein ◽  
Current Knowledge ◽  
Cholesterol Transport ◽  
Lipid Transfer ◽  
Complex Process ◽  
Associated Proteins ◽  
Membrane Contacts ◽  
Intracellular Cholesterol ◽  
Domain 3 ◽  
Steroidogenic Acute Regulatory

Intracellular cholesterol transport is a complex process involving specific carrier proteins. Cholesterol-binding proteins, such as the lipid transfer protein steroidogenic acute regulatory-related lipid transfer domain-3 (STARD3), are implicated in cholesterol movements between organelles. Indeed, STARD3 modulates intracellular cholesterol allocation by reducing it from the plasma membrane and favoring its passage from the endoplasmic reticulum (ER) to endosomes, where the protein is localized. STARD3 interacts with ER-anchored partners, notably vesicle-associated membrane protein-associated proteins (VAP-A and VAP-B) and motile sperm domain-containing 2 (MOSPD2), to create ER–endosome membrane contacts. Mechanistic studies showed that at ER–endosome contacts, STARD3 and VAP proteins build a molecular machine able to rapidly transfer cholesterol. This review presents the current knowledge on the molecular and cellular function of STARD3 in intracellular cholesterol traffic.

scholarly journals Advanced glycation end products affect cholesterol homeostasis by impairing ABCA1 expression on macrophages

2017 ◽  
Vol 95 (8) ◽  
pp. 977-984 ◽  
Author(s):  
Olivier Kamtchueng Simo ◽  
Souade Ikhlef ◽  
Hicham Berrougui ◽  
Abdelouahed Khalil
Keyword(s):  
Advanced Glycation End Products ◽  
Cholesterol Homeostasis ◽  
High Density Lipoproteins ◽  
Advanced Glycation ◽  
Cholesterol Levels ◽  
Glycation End Products ◽  
End Products ◽  
Prevention Of Atherosclerosis ◽  
Abca1 Protein

Reverse cholesterol transport (RCT), which is intimately linked to high-density lipoproteins (HDLs), plays a key role in cholesterol homeostasis and the prevention of atherosclerosis. The goal of the present study was to investigate the effect of aging and advanced glycation end products (AGEs) on RCT as well as on other factors that may affect the antiatherogenic property of HDLs. The transfer of macrophage-derived cholesterol to the plasma and liver and then to the feces for elimination was significantly lower in aged mice than in young mice. Chronic injection of d -galactose (D-gal) or AGEs also significantly reduced RCT (65.3% reduction in [3H]cholesterol levels in the plasma of D-gal-treated mice after 48 h compared with control mice, P < 0.01). The injection of both D-gal and aminoguanidine hydrochloride increased [3H]cholesterol levels in the plasma, although the levels were lower than those of control mice. The in vitro incubation of HDLs with dicarbonyl compounds increased the carbonyl and conjugated diene content of HDLs and significantly reduced PON1 paraoxonase activity (87.4% lower than control HDLs, P < 0.0001). Treating J774A.1 macrophages with glycated fetal bovine serum increased carbonyl formation (39.5% increase, P < 0.003) and reduced ABCA1 protein expression and the capacity of macrophages to liberate cholesterol (69.1% decrease, P < 0.0001). Our results showed, for the first time, that RCT is altered with aging and that AGEs contribute significantly to this alteration.

MLN64 and MENTHO, two mediators of endosomal cholesterol transport

2006 ◽  
Vol 34 (3) ◽  
pp. 343-345 ◽  
Author(s):  
F. Alpy ◽  
C. Tomasetto
Keyword(s):  
Metastatic Lymph Node ◽  
Regulatory Protein ◽  
Steroidogenic Acute Regulatory Protein ◽  
Cholesterol Transport ◽  
Lipid Transfer ◽  
Transmembrane Helices ◽  
Late Endosomes ◽  
Start Domain ◽  
Steroidogenic Acute Regulatory

MLN64 (metastatic lymph node 64) and MENTHO (MLN64 N-terminal homologue) are two late-endosomal proteins that share a conserved region of four transmembrane helices with three short intervening loops called the MENTAL domain (MLN64 N-terminal domain). This domain mediates MLN64 and MENTHO homo- and hetero-interactions, targets both proteins to late endosomes and binds cholesterol in vivo. In addition to the MENTAL domain, MLN64 contains a cholesterol-specific START domain [StAR (steroidogenic acute regulatory protein)-related lipid transfer domain]. The START domain is a protein module of approx. 210 residues that binds lipids, including sterols, and is present in 15 distinct proteins in mammals. Thus MLN64 and MENTHO define discrete cholesterol-containing subdomains within the membrane of late endosomes where they may function in cholesterol transport. The MENTAL domain might serve to maintain cholesterol at the membrane of late endosomes prior to its shuttle to cytoplasmic acceptor(s) through the START domain.

scholarly journals Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol

2021 ◽  
Vol 118 (33) ◽  
pp. e2102191118
Author(s):  
Hao Wang ◽  
Joshua A. Kulas ◽  
Chao Wang ◽  
David M. Holtzman ◽  
Heather A. Ferris ◽  
...  
Keyword(s):  
Genetic Risk ◽  
Cholesterol Synthesis ◽  
Amyloid Β ◽  
Cholesterol Transport ◽  
Targeted Deletion ◽  
Superresolution Imaging ◽  
Cholesterol Levels ◽  
Aβ Production

Alzheimer’s disease (AD) is characterized by the presence of amyloid β (Aβ) plaques, tau tangles, inflammation, and loss of cognitive function. Genetic variation in a cholesterol transport protein, apolipoprotein E (apoE), is the most common genetic risk factor for sporadic AD. In vitro evidence suggests that apoE links to Aβ production through nanoscale lipid compartments (lipid clusters), but its regulation in vivo is unclear. Here, we use superresolution imaging in the mouse brain to show that apoE utilizes astrocyte-derived cholesterol to specifically traffic neuronal amyloid precursor protein (APP) in and out of lipid clusters, where it interacts with β- and γ-secretases to generate Aβ-peptide. We find that the targeted deletion of astrocyte cholesterol synthesis robustly reduces amyloid and tau burden in a mouse model of AD. Treatment with cholesterol-free apoE or knockdown of cholesterol synthesis in astrocytes decreases cholesterol levels in cultured neurons and causes APP to traffic out of lipid clusters, where it interacts with α-secretase and gives rise to soluble APP-α (sAPP-α), a neuronal protective product of APP. Changes in cellular cholesterol have no effect on α-, β-, and γ-secretase trafficking, suggesting that the ratio of Aβ to sAPP-α is regulated by the trafficking of the substrate, not the enzymes. We conclude that cholesterol is kept low in neurons, which inhibits Aβ accumulation and enables the astrocyte regulation of Aβ accumulation by cholesterol signaling.

scholarly journals TDP-43 mediates SREBF2-regulated gene expression required for oligodendrocyte myelination

2021 ◽  
Vol 220 (9) ◽  
Author(s):  
Wan Yun Ho ◽  
Jer-Cherng Chang ◽  
Kenneth Lim ◽  
Amaury Cazenave-Gassiot ◽  
Aivi T. Nguyen ◽  
...  
Keyword(s):  
Cholesterol Metabolism ◽  
Cholesterol Biosynthesis ◽  
Cholesterol Homeostasis ◽  
Cholesterol Levels ◽  
The Central Nervous System ◽  
Cholesterol Supplementation ◽  
Regulated Gene Expression ◽  
Lateral Sclerosis

Cholesterol metabolism operates autonomously within the central nervous system (CNS), where the majority of cholesterol resides in myelin. We demonstrate that TDP-43, the pathological signature protein for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), influences cholesterol metabolism in oligodendrocytes. TDP-43 binds directly to mRNA of SREBF2, the master transcription regulator for cholesterol metabolism, and multiple mRNAs encoding proteins responsible for cholesterol biosynthesis and uptake, including HMGCR, HMGCS1, and LDLR. TDP-43 depletion leads to reduced SREBF2 and LDLR expression, and cholesterol levels in vitro and in vivo. TDP-43–mediated changes in cholesterol levels can be restored by reintroducing SREBF2 or LDLR. Additionally, cholesterol supplementation rescues demyelination caused by TDP-43 deletion. Furthermore, oligodendrocytes harboring TDP-43 pathology from FTD patients show reduced HMGCR and HMGCS1, and coaggregation of LDLR and TDP-43. Collectively, our results indicate that TDP-43 plays a role in cholesterol homeostasis in oligodendrocytes, and cholesterol dysmetabolism may be implicated in TDP-43 proteinopathies–related diseases.

scholarly journals Aberrantly high activation of a FoxM1–STMN1 axis contributes to progression and tumorigenesis in FoxM1-driven cancers

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Jun Liu ◽  
Jipeng Li ◽  
Ke Wang ◽  
Haiming Liu ◽  
Jianyong Sun ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Poor Prognosis ◽  
Soft Agar ◽  
Transcriptional Level ◽  
Regulation Mechanism ◽  
Strong Positive Correlation ◽  
Cell Viability Assay ◽  
High Level

AbstractFork-head box protein M1 (FoxM1) is a transcriptional factor which plays critical roles in cancer development and progression. However, the general regulatory mechanism of FoxM1 is still limited. STMN1 is a microtubule-binding protein which can inhibit the assembly of microtubule dimer or promote depolymerization of microtubules. It was reported as a major responsive factor of paclitaxel resistance for clinical chemotherapy of tumor patients. But the function of abnormally high level of STMN1 and its regulation mechanism in cancer cells remain unclear. In this study, we used public database and tissue microarrays to analyze the expression pattern of FoxM1 and STMN1 and found a strong positive correlation between FoxM1 and STMN1 in multiple types of cancer. Lentivirus-mediated FoxM1/STMN1-knockdown cell lines were established to study the function of FoxM1/STMN1 by performing cell viability assay, plate clone formation assay, soft agar assay in vitro and xenograft mouse model in vivo. Our results showed that FoxM1 promotes cell proliferation by upregulating STMN1. Further ChIP assay showed that FoxM1 upregulates STMN1 in a transcriptional level. Prognostic analysis showed that a high level of FoxM1 and STMN1 is related to poor prognosis in solid tumors. Moreover, a high co-expression of FoxM1 and STMN1 has a more significant correlation with poor prognosis. Our findings suggest that a general FoxM1-STMN1 axis contributes to cell proliferation and tumorigenesis in hepatocellular carcinoma, gastric cancer and colorectal cancer. The combination of FoxM1 and STMN1 can be a more precise biomarker for prognostic prediction.

Sign in / Sign up

Export Citation Format

Share Document