scholarly journals Fatty Aldehyde Dehydrogenase (ALDH3A2)-Dependent Neutralization of Advanced Lipid Peroxidation End Products (ALEs) at the Bifurcation of Hormetic and Degenerative Pathways in Pancreatic Beta Cells

Proceedings ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 10
Author(s):  
Sasson
Keyword(s):  
Lipid Peroxidation ◽  
Insulin Secretion ◽  
Palmitic Acid ◽  
Beta Cells ◽  
Aldehyde Dehydrogenase ◽  
Adaptive Response ◽  
Pancreatic Beta Cells ◽  
Fatty Aldehyde ◽  
End Products ◽  
And Function

Hyperglycemia and hyperlipidemia synergistically and adversely impair insulin secretion and ultimately lead to pancreatic beta cell decomposition. We found that both nutrient overload conditions displace arachidonic and linoleic acids from membrane phospholipids and subject them to free radical-mediated peroxidation and generation of advanced lipid peroxidation end products (ALEs), of which the aldehyde 4-hydroxy-2-nonenal (4-HNE) is prominent. When present at high levels this electrophilic molecule binds covalently to nucleophilic moieties in proteins, phospholipids and nucleic acid, modifies their structure and function and leads to severe cellular dysfunction and apoptosis. However, when present at low and unharmful levels this same molecule activates the nuclear receptor PPARδ and augments insulin secretion. The level of endogenous 4-HNE is determined by the extent of lipid peroxidation on one hand, and by enzymatic neutralization of the aldehyde, on the other. The latter step is mediated by enzymatic processes of which the transformation of the aldehyde to the corresponding inactive carboxylic derivative 4-hydroxy-2-nonenoic acid (4-HNA) is significant. The enzyme responsible for this transformation, which belongs to the large family of aldehyde dehydrogenases and selectively neutralizes fatty acid-derived aldehydes, is ALDH3A2, which is also known as fatty aldehyde dehydrogenase (FALDH). Consequently, we hypothesized that the expression level and function of ALDH3A2 may determine the fate of beta cells under nutrient overload conditions: insufficient neutralization of 4-HNE by the enzyme will lead to cell demise, whereas increased expression and function will extend the adaptive response of beta cells. This adaptive response that is characterized with increased insulin secretion enables effective storage of the nutrient surplus in peripheral tissues and organs while minimizing the dire consequences of the nutrient overload. We aimed at investigating the expression pattern of ALDH3A2 in pancreatic beta cells (the INS-1E cell line) under hyperglycemic condition without or with supplementation with saturated fatty acids (e.g., palmitic acid). Our results show significant glucose- and palmitic acid-dependent induction of ALDH3A2 expression in the cells. We also found that the transformation of palmitic acid (16:1) to mono-unsaturated palmitoleic acid (16:1, cis 9) by the enzyme Stearoyl-CoA desaturase-1 (SCD1) decreased the burden of the lipid stress on the cells and abrogated the stimulus for the induction of ALDH3A2. Preliminary experiments indicated that the upregulation of the induction of ALDH3A2 was partly induced by PPARδ. These findings correlate to our previous discovery that the hormetic effects of 4HNE were mediated via activation of this nuclear receptor. In summary, this study assigns a central role to the enzyme ALDH3A2 in the protective mechanism beta cells employ to mitigate detrimental effects of ALEs, and divert them into hormetic agents, that by feedback mechanism through PPARδ increase ALDH3A2 expression.

scholarly journals MicroRNAs Regulate the Wnt/Ca2+ Signaling Pathway to Promote the Secretion of Insulin in Pancreatic Nestin-Positive Progenitor Cells

2014 ◽  
Author(s):  
Chunyu Bai ◽  
Xiangchen Li ◽  
Yuhua Gao ◽  
Taofeng Lu ◽  
Kunfu Wang ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Progenitor Cells ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Target Genes ◽  
Cell Function ◽  
Expression Profiles ◽  
Control Cell ◽  
Small Noncoding Rnas ◽  
And Function

MicroRNAs (miRNAs) are small noncoding RNAs that bind to the 3?-UTR of mRNAs and function mainly in post-transcriptional regulation. MiRNAs have been implicated to play roles in organ development, including that of the pancreas. Many miRNAs, such as miR-375, miR-124, miR-7, miR-21 and miR-221, have been shown to regulate insulin production as well as insulin secretion. However, it is not known whether miRNAs can regulate insulin secretion via the control of intracellular Ca2+ in pancreatic beta cells. In this research, expression profiles of miRNAs and mRNAs were investigated using RNA-sequencing and microarray analysis in chicken pancreatic nestin-positive progenitor cells and differentiated pancreatic beta cells. A number of miRNAs were up-regulated after differentiation of progenitors into beta cells, which regulate cell signaling pathways to control cell function. miR-223 and miR146a were shown to promote insulin secretion from pancreatic beta cells by regulating the concentration of intracellular Ca2+ via the down-regulation of their target genes.

scholarly journals Activation of Aldehyde Dehydrogenase 2 Ameliorates Glucolipotoxicity of Pancreatic Beta Cells

Biomolecules ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1474
Author(s):  
Shiau-Mei Chen ◽  
Siow-Wey Hee ◽  
Shih-Yun Chou ◽  
Meng-Wei Liu ◽  
Che-Hong Chen ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Beta Cell ◽  
Beta Cells ◽  
Aldehyde Dehydrogenase ◽  
Mitochondrial Function ◽  
Beta Cell Function ◽  
Pancreatic Beta Cells ◽  
Cell Function ◽  
Aldehyde Dehydrogenase 2 ◽  
Min6 Cells

Chronic hyperglycemia and hyperlipidemia hamper beta cell function, leading to glucolipotoxicity. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) detoxifies reactive aldehydes, such as methylglyoxal (MG) and 4-hydroxynonenal (4-HNE), derived from glucose and lipids, respectively. We aimed to investigate whether ALDH2 activators ameliorated beta cell dysfunction and apoptosis induced by glucolipotoxicity, and its potential mechanisms of action. Glucose-stimulated insulin secretion (GSIS) in MIN6 cells and insulin secretion from isolated islets in perifusion experiments were measured. The intracellular ATP concentrations and oxygen consumption rates of MIN6 cells were assessed. Furthermore, the cell viability, apoptosis, and mitochondrial and intracellular reactive oxygen species (ROS) levels were determined. Additionally, the pro-apoptotic, apoptotic, and anti-apoptotic signaling pathways were investigated. We found that Alda-1 enhanced GSIS by improving the mitochondrial function of pancreatic beta cells. Alda-1 rescued MIN6 cells from MG- and 4-HNE-induced beta cell death, apoptosis, mitochondrial dysfunction, and ROS production. However, the above effects of Alda-1 were abolished in Aldh2 knockdown MIN6 cells. In conclusion, we reported that the activator of ALDH2 not only enhanced GSIS, but also ameliorated the glucolipotoxicity of beta cells by reducing both the mitochondrial and intracellular ROS levels, thereby improving mitochondrial function, restoring beta cell function, and protecting beta cells from apoptosis and death.

scholarly journals Pancreatic beta-cells expressing the Arg64 variant of the beta(3)-adrenergic receptor exhibit abnormal insulin secretory activity

2001 ◽  
Vol 27 (2) ◽  
pp. 133-144 ◽  
Author(s):  
R Perfetti ◽  
H Hui ◽  
K Chamie ◽  
S Binder ◽  
M Seibert ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Beta Cells ◽  
Western Blotting ◽  
Adrenergic Receptor ◽  
Pancreatic Beta Cells ◽  
Secretory Activity ◽  
Host Cells ◽  
Human Pancreas ◽  
Dependent Manner ◽  
Wild Type

The Arg64 beta(3)-adrenergic receptor (beta(3)AR) variant is associated with an earlier age of onset of diabetes and lower levels of insulin secretion in humans. The aims of this study were to investigate whether beta(3)AR is expressed by islet cells, if receptor binding affects insulin secretion and, finally, if the beta(3)AR Arg64 variant induces abnormal insulin secretory activity. Human pancreas extracts were subjected to RT-PCR, Western blotting and immunostaining analyses. DNA sequencing and Western blotting demonstrated that the beta(3)AR gene is transcribed and translated in the human pancreas; immunostaining showed that it is expressed by the islets of Langerhans. Cultured rat beta-cells responded to human beta(3)AR agonists in a dose- and time-dependent manner. Transfection of cultured rat beta-cells with the wild-type human beta(3)AR produced an increased baseline and ligand-dependent insulin secretion compared with parental cells. On the other hand, cells transfected with the Arg64 variant of the beta(3)AR secreted less insulin, both spontaneously and after exposure to human beta(3)AR agonists. Furthermore, while transfection with the wild-type beta(3)AR preserved the glucose-dependent secretion of insulin, expression of the variant receptor rendered the host cells significantly less responsive to glucose. In summary, cells express the beta(3)AR, and its activation contributes to the regulation of insulin secretion. These findings may help explain the low levels of insulin secretion in response to an i.v. glucose tolerance test observed in humans carrying the Arg64 polymorphism.

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