Effects of human serum albumin complexed with free fatty acids on cell viability and insulin secretion in the hamster pancreatic β-cell line HIT-T15

Tuei, Vivian C.; Ha, Ji-Sook; Ha, Chung-Eun

doi:10.1016/j.lfs.2011.02.022

Cited by 10 publications

(7 citation statements)

References 57 publications

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“…However, PA is usually tested as the representative saturated FA [1,4,30,31]. Interestingly, saturated FAs with a chain length shorter than 16 carbons, e.g., octanoate (8 carbons) and myristate (14 carbons), are ineffective as cell death inducers [6,35].…”

Section: Effects Of Fatty Acids On β-Cell Viability 21 Pro-apoptotic Effect Of Fatty Acidsmentioning

confidence: 99%

Molecular Mechanisms of Apoptosis Induction and Its Regulation by Fatty Acids in Pancreatic β-Cells

Šrámek

Němcová‐Fürstová

Kovář

2021

IJMS

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Pancreatic β-cell failure and death contribute significantly to the pathogenesis of type 2 diabetes. One of the main factors responsible for β-cell dysfunction and subsequent cell death is chronic exposure to increased concentrations of FAs (fatty acids). The effect of FAs seems to depend particularly on the degree of their saturation. Saturated FAs induce apoptosis in pancreatic β-cells, whereas unsaturated FAs are well tolerated and are even capable of inhibiting the pro-apoptotic effect of saturated FAs. Molecular mechanisms of apoptosis induction by saturated FAs in β-cells are not completely elucidated. Saturated FAs induce ER stress, which in turn leads to activation of all ER stress pathways. When ER stress is severe or prolonged, apoptosis is induced. The main mediator seems to be the CHOP transcription factor. Via regulation of expression/activity of pro- and anti-apoptotic Bcl-2 family members, and potentially also through the increase in ROS production, CHOP switches on the mitochondrial pathway of apoptosis induction. ER stress signalling also possibly leads to autophagy signalling, which may activate caspase-8. Saturated FAs activate or inhibit various signalling pathways, i.e., p38 MAPK signalling, ERK signalling, ceramide signalling, Akt signalling and PKCδ signalling. This may lead to the activation of the mitochondrial pathway of apoptosis, as well. Particularly, the inhibition of the pro-survival Akt signalling seems to play an important role. This inhibition may be mediated by multiple pathways (e.g., ER stress signalling, PKCδ and ceramide) and could also consequence in autophagy signalling. Experimental evidence indicates the involvement of certain miRNAs in mechanisms of FA-induced β-cell apoptosis, as well. In the rather rare situations when unsaturated FAs are also shown to be pro-apoptotic, the mechanisms mediating this effect in β-cells seem to be the same as for saturated FAs. To conclude, FA-induced apoptosis rather appears to be preceded by complex cross talks of multiple signalling pathways. Some of these pathways may be regulated by decreased membrane fluidity due to saturated FA incorporation. Few data are available concerning molecular mechanisms mediating the protective effect of unsaturated FAs on the effect of saturated FAs. It seems that the main possible mechanism represents a rather inhibitory intervention into saturated FA-induced pro-apoptotic signalling than activation of some pro-survival signalling pathway(s) or metabolic interference in β-cells. This inhibitory intervention may be due to an increase of membrane fluidity.

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Section: Effects Of Fatty Acids On β-Cell Viability 21 Pro-apoptotic Effect Of Fatty Acidsmentioning

confidence: 99%

Molecular Mechanisms of Apoptosis Induction and Its Regulation by Fatty Acids in Pancreatic β-Cells

Šrámek

Němcová‐Fürstová

Kovář

2021

IJMS

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“…Supplementation of cultured cells with FFAs produces oxidative stress, and treatment of these cells with antioxidants inhibits FFA-induced caspase-3 activation, ER dysfunction, and cell death (46 -48). Supplementation of cultured fibroblasts, myoblasts, and ␤ cells with FFAs leads to alterations in the structure and function of the ER that precede the activation of ER stress responses (49). Autophagy may play an important role in the response to ER stress and has been implicated as a con- tributing factor to apoptosis and cell death (27,30).…”

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confidence: 99%

The Transcription Factor p8 Regulates Autophagy in Response to Palmitic Acid Stress via a Mammalian Target of Rapamycin (mTOR)-independent Signaling Pathway

Jia¹,

Lin²,

Chen

et al. 2016

Journal of Biological Chemistry

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Autophagy is an evolutionarily conserved degradative process that allows cells to maintain homoeostasis in numerous physiological situations. This process also functions as an essential protective response to endoplasmic reticulum (ER) stress, which promotes the removal and degradation of unfolded proteins. However, little is known regarding the mechanism by which autophagy is initiated and regulated in response to ER stress. In this study, different types of autophagy were identified in human gastric cancer MKN45 cells in response to the stress induced by nutrient starvation or lipotoxicity in which the regulation of these pathways is mammalian target of rapamycin (mTOR)-dependent or -independent, respectively. Interestingly, we found that p8, a stress-inducible transcription factor, was enhanced in MKN45 cells treated with palmitic acid to induce lipotoxicity. Furthermore, an increase in autophagy was observed in MKN45 cells stably overexpressing p8 using a lentivirus system, and autophagy induced by palmitic acid was blocked by p8 RNAi compared with the control. Western blotting analyses showed that autophagy was regulated by p8 or mTOR in response to the protein kinase-like endoplasmic reticulum kinase/activating transcription factor 6-mediated ER stress of lipotoxicity or the parkin-mediated mitochondrial stress of nutrient starvation, respectively. Furthermore, our results indicated that autophagy induced by palmitic acid is mTOR-independent, but this autophagy pathway was regulated by p8 via p53-and PKC␣-mediated signaling in MKN45 cells. Our findings provide insights into the role of p8 in regulating autophagy induced by the lipotoxic effects of excess fat accumulation in cells.Autophagy is a phenomenon in which cytoplasmic components are delivered to the lysosomes for bulk degradation in response to prolonged starvation periods, nutritional fluctuations in the environment, developmental tissue remodeling, organelle quality control, or immune responses (1-3). Recent studies have shown that the dysregulation of autophagy is implicated in the physiopathology of major diseases such as cancer, neurodegenerative disorders, and diabetes (4 -8). The autophagy process involves more than 30 autophagy-related genes and can be divided into several physiologically continuous steps (including induction, cargo recognition and packaging, and vesicle formation and breakdown) (9 -11). As a key energy sensor, AMP-activated protein kinase (AMPK) 3 regulates the cellular metabolism to maintain energy homoeostasis and promotes autophagy by activating UNC-51-like kinase 1 (ULK1) through the phosphorylation of its Ser-317 and Ser-777 residues. Conversely, the central cell growth regulator mammalian target of rapamycin (mTOR) inhibits autophagy by phosphorylating Ser-757 of ULK1 and disrupting its interaction with AMPK (12-16). This coordinated pattern of phosphorylation is important for the proper control of autophagy.Autophagy can be nonselective or selective. Non-selective bulk degradation of the cytoplasm and organelles by ...

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“…Interestingly, albumin-bound oleate did not induce this increase in oxidative stress and apoptosis, and even attenuated palmitate-induced oxidative stress and apoptosis [ 77 ]. Additionally, FFAs have a lipotoxic effect on pancreatic β-cells, contributing to impaired insulin production in obese patients [ 78 , 79 ]. Moreover, albumin polymorphisms reduced β-cell cytotoxicity by increasing affinity of palmitate and oleate binding [ 78 ].…”

Section: Albumin and Ffasmentioning

confidence: 99%

Albumin is an interface between blood plasma and cell membrane, and not just a sponge

Wouw

Joles

2021

Clinical Kidney Journal

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Albumin is the most abundant protein in blood plasma and acts as a carrier for many circulating molecules. Hypoalbuminemia, mostly caused by either renal or liver disease or malnutrition, can perturb vascular homeostasis and is involved in development of multiple diseases. Here we review four functions of albumin and the consequences of hypoalbuminemia on vascular homeostasis. (i) Albumin is the main determinant of plasma colloid-osmotic pressure. Hypoalbuminemia was therefore thought to be the main mechanism for edema in nephrotic syndrome, however experimental studies showed that intrarenal mechanisms rather than hypoalbuminemia determine formation and in particular maintenance of edema. (ii) Albumin functions as an interface between lysophosphatidylcholine (LPC) and circulating factors (lipoproteins and erythrocytes) and the endothelium. Consequently, hypoalbuminemia results in higher LPC levels in lipoproteins and erythrocyte membrane, thereby increasing atherosclerotic properties of low-density lipoprotein and blood viscosity, respectively. Furthermore, albumin dose-dependently restores LPC-induced inhibition of vasodilation. (iii) Hypoalbuminemia impacts on vascular nitric oxide (NO) signaling by directly increasing NO-production in endothelial cells, leading to reduced NO-sensitivity of vascular smooth muscle cells. (iv) Lastly, albumin binds free fatty acids (FFA). FFA can induce vascular smooth muscle cell apoptosis, uncouple endothelial NO synthase and decrease endothelium-dependent vasodilation. Unbound FFA can increase formation of reactive oxygen species by mitochondrial uncoupling in multiple cell types and induce hypertriglyceridemia in nephrotic syndrome. In conclusion, albumin acts as an interface in the circulation and hypoalbuminemia impairs multiple aspects of vascular function which may underlie the association of hypoalbuminemia with adverse outcomes. However, hypoalbuminemia is not key to edema in nephrotic syndrome. These insights have therapeutic implications.

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Effects of human serum albumin complexed with free fatty acids on cell viability and insulin secretion in the hamster pancreatic β-cell line HIT-T15

Cited by 10 publications

References 57 publications

Molecular Mechanisms of Apoptosis Induction and Its Regulation by Fatty Acids in Pancreatic β-Cells

Molecular Mechanisms of Apoptosis Induction and Its Regulation by Fatty Acids in Pancreatic β-Cells

The Transcription Factor p8 Regulates Autophagy in Response to Palmitic Acid Stress via a Mammalian Target of Rapamycin (mTOR)-independent Signaling Pathway

Albumin is an interface between blood plasma and cell membrane, and not just a sponge

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