The role of endosomal cholesterol trafficking protein, StAR-related lipid transfer domain 3 (StarD3/MLN64), in BRIN-BD11 insulinoma cells

Pinto, Joana Borges; Graham, Annette

doi:10.1007/s13238-016-0315-0

Cited by 6 publications

(5 citation statements)

References 15 publications

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“…Overexpression of Cyp27A1 in BRIN-BD11 cells did not affect the biosynthesis, esterification or efflux of cholesterol under basal conditions but enhanced efflux to ApoA-I and human serum in cells previously exposed to native LDL. These findings resonate with our previous study, which suggested that rapidly proliferating BRIN-BD11 cells have suboptimal levels of cholesterol [ 47 ], and with that of Fu et al [ 24 ], who demonstrated enhanced induction of LXR-dependent genes involved in the cholesterol efflux pathway in cholesterol-loaded Cyp27-expressing cells, compared with controls. However, ligation of TSPO, using FGIN-1-27, had no impact on the cholesterol efflux pathway in stable populations of Cyp27A1 or EV BRIN-BD11 cells.…”

Section: Discussionsupporting

confidence: 92%

“…These putative relationships were explored further in rodent BRIN-BD11 insulinoma cells; while human pancreatic islets and β-cells are known to express CYP27A1, rodent insulinoma cells do not, indicating that this protein is not an essential requirement for glucose-stimulated insulin secretion [ 43 ]. However, insulin release in BRIN-BD11 cells is responsive to modulation of cholesterol content [ 47 ] providing a suitable cellular context in which to examine the relationship between cholesterol trafficking and metabolising proteins and the cholesterol efflux pathway.…”

Section: Resultsmentioning

confidence: 99%

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Genetic obesity increases pancreatic expression of mitochondrial proteins which regulate cholesterol efflux in BRIN-BD11 insulinoma cells

et al. 2019

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Pancreatic β-cells are sensitive to fluctuations in cholesterol content, which can damage the insulin secretion pathway, contributing to the aetiology of type 2 diabetes mellitus. Cholesterol efflux to (apo)lipoproteins, via ATP-binding cassette (ABC) transporter A1 (ABCA1), can prevent intracellular cholesterol accumulation; in some peripheral cells, ABCA1-dependent efflux is enhanced by promotion of cholesterol trafficking to, and generation of Liver X receptor (LXR) ligands by, mitochondrial sterol 27-hydroxylase (Cyp27A1 (cytochrome P450 27 A1/sterol 27-hydroxylase)) and its redox partners, adrenodoxin (ADX) and ADX reductase (ADXR). Despite this, the roles of mitochondrial cholesterol trafficking (steroidogenic acute regulatory protein [StAR] and 18-kDa translocator protein [TSPO]) and metabolising proteins in insulin-secreting cells remain wholly uncharacterised. Here, we demonstrate an increase in pancreatic expression of Cyp27A1, ADXR, TSPO and LXRα, but not ADX or StAR, in obese (fa/fa) rodents compared with lean (Fa/?) controls. Overexpression of Cyp27A1 alone in BRIN-BD11 cells increased INS2 expression, without affecting lipid metabolism; however, after exposure to low-density lipoprotein (LDL), cholesterol efflux to (apo)lipoprotein acceptors was enhanced in Cyp27A1-overexpressing cells. Co-transfection of Cyp27A1, ADX and ADXR, at a ratio approximating that in pancreatic tissue, stimulated cholesterol efflux to apolipoprotein A-I (apoA-I) in both basal and cholesterol-loaded cells; insulin release was stimulated equally by all acceptors in cholesterol-loaded cells. Thus, genetic obesity increases pancreatic expression of Cyp27A1, ADXR, TSPO and LXRα, while modulation of Cyp27A1 and its redox partners promotes cholesterol efflux from insulin-secreting cells to acceptor (apo)lipoproteins; this response may help guard against loss of insulin secretion caused by accumulation of excess intracellular cholesterol.

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Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Genetic obesity increases pancreatic expression of mitochondrial proteins which regulate cholesterol efflux in BRIN-BD11 insulinoma cells

et al. 2019

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“…When excessive cholesterol accumulated on the mitochondrial membrane, the transport of L-Glutathione (GSH) to the mitochondria was impaired, which led to less mitochondrial ROS depletion [16]. During the trafficking progress, Stard3 could provide a binding site for cholesterol trafficking [24]. Elisa Balboa showed the upregulation of Stard3 could transport cholesterol to mitochondria, which induced cholesterol accumulation on mitochondria [16].…”

Section: Discussionmentioning

confidence: 99%

Knocking down Stard3 decreases adipogenesis with decreased mitochondrial ROS in 3T3-L1 cells

Zhou

Gao

Guo

et al. 2018

Biochemical and Biophysical Research Communications

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Start domain-containing protein 3 (Stard3) plays roles in intracellular cholesterol distribution, however, the role of Stard3 in the adipogenesis of 3T3-L1 preadipocytes remains unclear. We demonstrated that Stard3 expression was significantly increased during the adipogenesis of 3T3-L1 preadipocytes, accompanied by an increase of mitochondrial Reactive oxygen species (ROS). Stard3 knocking-down inhibited 3T3-L1 preadipocyte adipogenesis with decreased mitochondrial ROS levels, while ROS inducer rescued the stard3 silencing 3T3 cells with increased ROS. Moreover, Stard3 silencing reduced the expression of peroxisome proliferator-activated receptor-γ (PPARγ) and CCAAT/enhancer binding protein (C/EBP)α in 3T3- L1 cells. In conclusion, Stard3 enhanced the adipogenesis of preadipocytes by enhancement of cholesterol redistribution to the mitochondrial, increasing mitochondrial ROS production. These results suggest that Stard3 is an essential factor for the 3T3-L1 cells' differentiation.

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“…In line with this, STARD3 protein levels are correlated with lutein concentrations in the human brain ( Tanprasertsuk et al, 2016 ). On the other hand, in insulinoma cells, it has been observed that the expression of STARD3 is not regulated by lutein ( Pinto and Graham, 2016 ). However, this observation lacks clarity regarding the methodology employed for lutein administration, such as direct addition or incorporation via liposomes, as well as the duration of treatment.…”

Section: The Lutein-binding Protein Stard3mentioning

confidence: 99%

Exploring the lutein therapeutic potential in steatotic liver disease: mechanistic insights and future directions

Balboa,

Saud,

Parra-Ruiz

et al. 2024

Front. Pharmacol.

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The global prevalence of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is increasing, now affecting 25%–30% of the population worldwide. MASLD, characterized by hepatic steatosis, results from an imbalance in lipid metabolism, leading to oxidative stress, lipoperoxidation, and inflammation. The activation of autophagy, particularly lipophagy, alleviates hepatic steatosis by regulating intracellular lipid levels. Lutein, a carotenoid with antioxidant and anti-inflammatory properties, protects against liver damage, and individuals who consume high amounts of lutein have a lower risk of developing MASLD. Evidence suggests that lutein could modulate autophagy-related signaling pathways, such as the transcription factor EB (TFEB). TFEB plays a crucial role in regulating lipid homeostasis by linking autophagy to energy metabolism at the transcriptional level, making TFEB a potential target against MASLD. STARD3, a transmembrane protein that binds and transports cholesterol and sphingosine from lysosomes to the endoplasmic reticulum and mitochondria, has been shown to transport and bind lutein with high affinity. This protein may play a crucial role in the uptake and transport of lutein in the liver, contributing to the decrease in hepatic steatosis and the regulation of oxidative stress and inflammation. This review summarizes current knowledge on the role of lutein in lipophagy, the pathways it is involved in, its relationship with STARD3, and its potential as a pharmacological strategy to treat hepatic steatosis.

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The role of endosomal cholesterol trafficking protein, StAR-related lipid transfer domain 3 (StarD3/MLN64), in BRIN-BD11 insulinoma cells

Cited by 6 publications

References 15 publications

Genetic obesity increases pancreatic expression of mitochondrial proteins which regulate cholesterol efflux in BRIN-BD11 insulinoma cells

Genetic obesity increases pancreatic expression of mitochondrial proteins which regulate cholesterol efflux in BRIN-BD11 insulinoma cells

Knocking down Stard3 decreases adipogenesis with decreased mitochondrial ROS in 3T3-L1 cells

Exploring the lutein therapeutic potential in steatotic liver disease: mechanistic insights and future directions

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