Perilipin 5 Reduces Oxidative Damage Associated With Lipotoxicity by Activating the PI3K/ERK-Mediated Nrf2-ARE Signaling Pathway in INS-1 Pancreatic β-Cells

Zhu, Yunxia; Ren, Chen-Xi; Zhang, Mingliang; Zhong, Yuan

doi:10.3389/fendo.2020.00166

Cited by 27 publications

(22 citation statements)

References 59 publications

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“…One possible explanation of the decline in Nrf2 and HO-1 activity is through the downregulation of PI3K/AKT pathway under conditions of oxidative stress. PI3K/AKT activation is thought to induce Nrf2, and thus its downregulation would continually decrease Nrf2 activation [129].…”

Section: Antioxidant Properties Of β Cellsmentioning

confidence: 99%

The Role of Oxidative Stress in Pancreatic β Cell Dysfunction in Diabetes

Eguchi

Vaziri

Dafoe

et al. 2021

IJMS

184

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Diabetes is a chronic metabolic disorder characterized by inappropriately elevated glucose levels as a result of impaired pancreatic β cell function and insulin resistance. Extensive studies have been conducted to elucidate the mechanism involved in the development of β cell failure and death under diabetic conditions such as hyperglycemia, hyperlipidemia, and inflammation. Of the plethora of proposed mechanisms, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and oxidative stress have been shown to play a central role in promoting β cell dysfunction. It has become more evident in recent years that these 3 factors are closely interrelated and importantly aggravate each other. Oxidative stress in particular is of great interest to β cell health and survival as it has been shown that β cells exhibit lower antioxidative capacity. Therefore, this review will focus on discussing factors that contribute to the development of oxidative stress in pancreatic β cells and explore the downstream effects of oxidative stress on β cell function and health. Furthermore, antioxidative capacity of β cells to counteract these effects will be discussed along with new approaches focused on preserving β cells under oxidative conditions.

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Section: Antioxidant Properties Of β Cellsmentioning

confidence: 99%

The Role of Oxidative Stress in Pancreatic β Cell Dysfunction in Diabetes

Eguchi

Vaziri

Dafoe

et al. 2021

IJMS

184

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“…In basal state, Plin1 and Plin5 participate to accumulate palmitate into triglycerides to limit its utilization by the mitochondria, by inhibiting hydrolysis and stabilizing the lipid droplet. In starvation, as consequence of protein kinase A-stimulated triggering, LD hydrolysis inhibition is lifted, and FAs are released from LDs to undergo β-oxidation in mitochondria ( 47 , 48 ). This is associated to a transcriptional signaling, as well.…”

Section: Mitochondria and Cancer Cell Bioenergeticsmentioning

confidence: 99%

Mitochondrial Bioenergetics at the Onset of Drug Resistance in Hematological Malignancies: An Overview

et al. 2020

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The combined derangements in mitochondria network, function and dynamics can affect metabolism and ATP production, redox homeostasis and apoptosis triggering, contributing to cancer development in many different complex ways. In hematological malignancies, there is a strong relationship between cellular metabolism, mitochondrial bioenergetics, interconnections with supportive microenvironment and drug resistance. Lymphoma and chronic lymphocytic leukemia cells, e.g., adapt to intrinsic oxidative stress by increasing mitochondrial biogenesis. In other hematological disorders such as myeloma, on the contrary, bioenergetics changes, associated to increased mitochondrial fitness, derive from the adaptive response to drug-induced stress. In the bone marrow niche, a reverse Warburg effect has been recently described, consisting in metabolic changes occurring in stromal cells in the attempt to metabolically support adjacent cancer cells. Moreover, a physiological dynamic, based on mitochondria transfer, between tumor cells and their supporting stromal microenvironment has been described to sustain oxidative stress associated to proteostasis maintenance in multiple myeloma and leukemia. Increased mitochondrial biogenesis of tumor cells associated to acquisition of new mitochondria transferred by mesenchymal stromal cells results in augmented ATP production through increased oxidative phosphorylation (OX-PHOS), higher drug resistance, and resurgence after treatment. Accordingly, targeting mitochondrial biogenesis, electron transfer, mitochondrial DNA replication, or mitochondrial fatty acid transport increases therapy efficacy. In this review, we summarize selected examples of the mitochondrial derangements in hematological malignancies, which provide metabolic adaptation and apoptosis resistance, also supported by the crosstalk with tumor microenvironment. This field promises a rational design to improve target-therapy including the metabolic phenotype.

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“…While the regulation of mitogen-activated protein kinase (MAPK) pathway including JNK and extracellular-signal-regulated kinase (ERK) as well as Pi3K/Akt pathway are undoubtedly essential for cell survival, there are contrasting data regarding their exact role for the β-cell. According to literature, effects differ crucially between cell types and highly depend on the chosen treatment conditions [ 132 , 183 ], e.g., PA inhibited ERK and induced apoptosis in INS-1 cells [ 184 ], but exposure of glucose and interleukin (IL)-1β triggered apoptosis concomitant with elevated ERK levels in human β-cells [ 44 , 185 ].…”

Section: Lipotoxic Action Of Ffa On Mitochondria In β-Cellsmentioning

confidence: 99%

Lipotoxic Impairment of Mitochondrial Function in β-Cells: A Review

2021

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Lipotoxicity is a major contributor to type 2 diabetes mainly promoting mitochondrial dysfunction. Lipotoxic stress is mediated by elevated levels of free fatty acids through various mechanisms and pathways. Impaired peroxisome proliferator-activated receptor (PPAR) signaling, enhanced oxidative stress levels, and uncoupling of the respiratory chain result in ATP deficiency, while β-cell viability can be severely impaired by lipotoxic modulation of PI3K/Akt and mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK) pathways. However, fatty acids are physiologically required for an unimpaired β-cell function. Thus, preparation, concentration, and treatment duration determine whether the outcome is beneficial or detrimental when fatty acids are employed in experimental setups. Further, ageing is a crucial contributor to β-cell decay. Cellular senescence is connected to loss of function in β-cells and can further be promoted by lipotoxicity. The potential benefit of nutrients has been broadly investigated, and particularly polyphenols were shown to be protective against both lipotoxicity and cellular senescence, maintaining the physiology of β-cells. Positive effects on blood glucose regulation, mitigation of oxidative stress by radical scavenging properties or regulation of antioxidative enzymes, and modulation of apoptotic factors were reported. This review summarizes the significance of lipotoxicity and cellular senescence for mitochondrial dysfunction in the pancreatic β-cell and outlines potential beneficial effects of plantbased nutrients by the example of polyphenols.

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Perilipin 5 Reduces Oxidative Damage Associated With Lipotoxicity by Activating the PI3K/ERK-Mediated Nrf2-ARE Signaling Pathway in INS-1 Pancreatic β-Cells

Cited by 27 publications

References 59 publications

The Role of Oxidative Stress in Pancreatic β Cell Dysfunction in Diabetes

The Role of Oxidative Stress in Pancreatic β Cell Dysfunction in Diabetes

Mitochondrial Bioenergetics at the Onset of Drug Resistance in Hematological Malignancies: An Overview

Lipotoxic Impairment of Mitochondrial Function in β-Cells: A Review

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