Non-esterified fatty acids activate the ROS–p38–p53/Nrf2 signaling pathway to induce bovine hepatocyte apoptosis in vitro

Published on Apr 4, 2014in Apoptosis4.543
· DOI :10.1007/S10495-014-0982-3
Yuxiang Song8
Estimated H-index: 8
(JLU: Jilin University),
Xinwei Li23
Estimated H-index: 23
(JLU: Jilin University)
+ 7 AuthorsZhe Wang26
Estimated H-index: 26
(JLU: Jilin University)
Sources
Abstract
A high plasma concentration of non-esterified fatty acids (NEFAs) is an important pathogenic factor that leads to ketosis and fatty liver in dairy cows. NEFAs may be associated with oxidative stress in dairy cows with ketosis or fatty liver and the subsequent induction of hepatocyte damage. However, the molecular mechanism of NEFAs-induced oxidative stress and whether NEFAs cause apoptosis of hepatocytes are unclear. Therefore, the aim of this study was to investigate the molecular mechanism of NEFAs-induced oxidative liver damage in bovine hepatocytes. The results showed that NEFAs increased oxidative stress, resulting in p38 phosphorylation. High activated p38 increased the expression, nuclear localization and transcriptional activity of p53 and decreased the nuclear localization and transcriptional activity of Nrf2 in bovine hepatocytes treated with high concentrations of NEFAs. High concentrations of NEFAs also promoted the apoptosis of bovine hepatocytes. Both N-acetyl-l-cysteine (NAC) and glucose (GLU) could attenuate the NEFA-induced apoptotic damage. These results indicate that NEFAs activate the ROS–p38–p53/Nrf2 signaling pathway to induce apoptotic damage in bovine hepatocytes.
📖 Papers frequently viewed together
113 Citations
9 Citations
109 Citations
References37
Newest
#1Ana M. Tormos (University of Valencia)H-Index: 8
#2Raquel Taléns-Visconti (University of Valencia)H-Index: 10
Last. Juan Sastre (University of Valencia)H-Index: 65
view all 4 authors...
Abstractp38 MAPKs are important mediators of signal transduction that respond to a wide range of extracellular stressors such as UV radiation, osmotic shock, hypoxia, pro-inflammatory cytokines, and oxidative stress. The most abundant family member is p38α, which helps to couple cell proliferation and growth in response to certain damaging stimuli. In fact, increased proliferation and impaired differentiation are hallmarks of p38α-deficient cells. It has been reported that reactive oxygen specie...
60 CitationsSource
#1Zhigang ZhangH-Index: 24
#2Xiaobing Li (JLU: Jilin University)H-Index: 22
Last. Ri-He Zhang (JLU: Jilin University)H-Index: 1
view all 10 authors...
Abstract Primary hepatocytes are commonly used during in vitro studies, but care must be taken with isolation and culture of the cells to ensure their viability. In this study, hepatocytes were isolated from the liver (caudate process) of a newborn calf by the collagenase perfusion and digestion method. The trypan blue exclusion method was used to determine total cell number and the survival rate of hepatocytes, while hepatocyte function was assessed by measuring lactate dehydrogenase, albumin a...
25 CitationsSource
#1Huangyuan Li (Fujian Medical University)H-Index: 15
#2Siying Wu (Fujian Medical University)H-Index: 14
Last. Wei Lin (Fujian Medical University)H-Index: 3
view all 5 authors...
Manganese has been known to induce neurological disorders similar to Parkinson's disease. One of the features of manganese-induced neurotoxicity is oxidative stress. Accumulating data implicate NF-E2-related factor 2 (Nrf2) as a key regulator in the adaptive survival response to oxidative stress. Recent studies suggest that the activation of Nrf2 is induced by manganese in PC12 cells. In the present study, we investigated possible links between reactive oxygen species (ROS), proteasome or mitoge...
46 CitationsSource
#1G. Andres Contreras (MSU: Michigan State University)H-Index: 12
#2Lorraine M. Sordillo (MSU: Michigan State University)H-Index: 55
The transition period of dairy cattle is characterized by dramatic changes in metabolism and host defense mechanisms that are associated with increased disease. Intense lipid mobilization from tissue stores is an important metabolic adaptation during the transition period that results in significant release of non-esterified fatty acids (NEFA) into the blood stream. Whereas these fatty acids are important sources of energy during times of increased metabolic demands, elevated concentrations of N...
137 CitationsSource
#1D. Claire Wathes (RVC: Royal Veterinary College)H-Index: 23
#2Zhangrui ChengH-Index: 24
Last. Joe PattonH-Index: 15
view all 5 authors...
Postpartum dairy cows enter a period of negative energy balance (NEB) associated with low circulating IGF1, during which the uterus must undergo extensive repair following calving. This study investigated the effects of NEB on expression of IGF family members and related genes in the involuting uterus. Cows were allocated to two treatments using differential feeding and milking regimes to produce mild NEB or severe NEB (SNEB). Uterine endometrial samples collected 2 weeks post partum were analys...
86 CitationsSource
#1Huiping Yuan (PKU: Peking University)H-Index: 2
#2Xiaoyong Zhang (Peking Union Medical College)H-Index: 1
Last. Jian Jian Li (PKU: Peking University)H-Index: 3
view all 9 authors...
Dysfunction of β-cell is one of major characteristics in the pathogenesis of type 2 diabetes. The combination of obesity and type 2 diabetes, characterized as ‘diabesity’, is associated with elevated plasma free fatty acids (FFAs). Oxidative stress has been implicated in the pathogenesis of FFA-induced β-cell dysfunction. However, molecular mechanisms linking between reactive oxygen species (ROS) and FFA-induced β-cell dysfunction and apoptosis are less clear. In the present study, we test the h...
96 CitationsSource
#1Shin Oikawa (Rakuno Gakuen University)H-Index: 11
#1Shin Oikawa (Rakuno Gakuen University)H-Index: 11
Last. Mohamed TharwatH-Index: 14
view all 4 authors...
The purpose of this study was to evaluate changes of very low-density lipoprotein (VLDL) components in hepatic blood (HB) from 5 nonlactating nonpregnant cows fasted from days 0 to 3 and subsequently refed to day 10 and, in addition, to assess those of other lipoproteins. Increased phospholipid concentrations in each lipoprotein after the start of fasting suggested their availability for the surface lipids of lipoproteins. Although the VLDL-triglyceride (TG) concentration in HB from all cows inc...
21 Citations
Abstract Reactive oxygen species (ROS) are products of normal metabolism and xenobiotic exposure, and depending on their concentration, ROS can be beneficial or harmful to cells and tissues. At physiological low levels, ROS function as “redox messengers” in intracellular signaling and regulation, whereas excess ROS induce oxidative modification of cellular macromolecules, inhibit protein function, and promote cell death. Additionally, various redox systems, such as the glutathione, thioredoxin, ...
2,131 CitationsSource
#1John D. Hayes (Dund.: University of Dundee)H-Index: 95
#2Michael T. McMahon (Dund.: University of Dundee)H-Index: 45
Last. Michael McMahon (Dund.: University of Dundee)H-Index: 23
view all 2 authors...
Transcription factor nuclear factor-erythroid 2-related factor 2 (NRF2) controls cellular adaptation to oxidants and electrophiles by inducing antioxidant and detoxification genes in response to redox stress. NRF2 is negatively regulated by Kelch-like ECH-associated protein 1 (KEAP1). Tumours from ∼15% of patients with lung cancer harbour somatic mutations in KEAP1 that prevent effective NRF2 repression. Recently, two NRF2 mutation ‘hot-spots' were identified in ∼10% of patients with lung cancer...
661 CitationsSource
#1Bingxuan Liu (Sichuan University)H-Index: 135
#1Bo Liu (Sichuan University)H-Index: 56
Last. Jin-ku Bao (Sichuan University)H-Index: 17
view all 5 authors...
Abstract Polygonatum cyrtonema lectin (PCL), a mannose-binding lectin, has been reported to induce cytotoxicity and apoptosis. Herein, we demonstrated that PCL-induced apoptosis and autophagy in A375 cells. The apoptotic mechanism was that PCL treatment regulated Bax, Bcl-xL and Bcl-2 proteins, leading to mitochondrial depolarization, cytochrome c release and caspase activation. Subsequently, we found that PCL treatment abrogated glutathione antioxidant system and induced mitochondria to generat...
165 CitationsSource
Cited By55
Newest
#1Ahmed A. ElolimyH-Index: 8
#2Yusheng Liang (UIUC: University of Illinois at Urbana–Champaign)H-Index: 8
Last. Juan J. Loor (UIUC: University of Illinois at Urbana–Champaign)H-Index: 68
view all 4 authors...
ABSTRACT null null The dairy industry worldwide is confronting unprecedented challenges including climate change and consistently increasing feed costs, the latter representing a major issue for dairy farmers. Thus, renewed efforts for improving feed efficiency by focusing on biological components within the rumen and peripheral tissues of the animal that contribute to feed efficiency are taking center stage. These efforts have been made possible by the growing application of cutting-edge techno...
Source
#1Yan Huang (NWAFU: Northwest A&F University)H-Index: 2
#2Jing Wen (NWAFU: Northwest A&F University)H-Index: 1
Last. Baoyu Zhao (NWAFU: Northwest A&F University)H-Index: 5
view all 12 authors...
Background null A better comprehension of the redox status during the periparturient period may facilitate the development of management and nutritional solutions to prevent subclinical hyperketonemia (SCHK) and subclinical hypocalcemia (SCHC) in dairy goats. We aimed to evaluate the variation in the redox status of dairy goats with SCHK and SCHC during their periparturient periods. Guanzhong dairy goats (n = 30) were assigned to SCHK (n = 10), SCHC (n = 10), and healthy (HEAL, n = 10) groups ba...
Source
#1Tianle Xu (YZU: Yangzhou University)H-Index: 10
#2Xubin Lu (YZU: Yangzhou University)H-Index: 5
Last. Zhangping Yang (YZU: Yangzhou University)H-Index: 10
view all 7 authors...
The occurrence of bovine ketosis involves the accumulation of β-hydroxybutyric acid (BHBA), which contributes to the initiation and acceleration of hepatic metabolic stress and inflammation. Metformin has other beneficial effects apart from its medical intervention for diabetes, such as prevention of laminitis and hyper-triglyceridemic. AMPK maintains energy homeostasis and is the intracellular target of metformin action. This study aims to uncover the role of metformin in modulating BHBA-induce...
Source
#1Lei Wang (CAS: Chinese Academy of Sciences)H-Index: 101
#2Jiaxin Lin (CAS: Chinese Academy of Sciences)
Last. Lei Pan (CAS: Chinese Academy of Sciences)H-Index: 10
view all 7 authors...
Lipid droplets (LDs) are dynamic intracellular organelles critical for lipid metabolism. Alterations in the dynamics and functions of LDs during innate immune response to infections and the underlying mechanisms however, remain largely unknown. Herein, we describe the morphological dynamics of LDs in fat body of Drosophila, which vary between transient and sustained bacterial infections. Detailed analysis shows that perilipin1 (plin1), a core gene regulating lipid metabolism of LDs is suppressed...
Source
#1Taiyu Shen (JLU: Jilin University)H-Index: 5
#2Feng Xu (JLU: Jilin University)H-Index: 1
Last. Guowen Liu (JLU: Jilin University)H-Index: 27
view all 17 authors...
ABSTRACT Severe negative energy balance around parturition is an important contributor to ketosis, a metabolic disorder that occurs most frequently in the peripartal period. Autophagy and mitophagy are important processes responsible for breaking down useless or toxic cellular material, and in particular damaged mitochondria. However, the role of autophagy and mitophagy during the occurrence and development of ketosis is unclear. The objective of this study was to investigate autophagy and mitop...
Source
#1Michał Otręba (Medical University of Silesia)H-Index: 11
#2Johanna J. Sjölander (University of Gothenburg)H-Index: 2
Last. Per Sunnerhagen (University of Gothenburg)H-Index: 29
view all 4 authors...
Small molecules are routinely used to inhibit protein kinases, but modulators capable of enhancing kinase activity are rare. We have previously shown that the small molecule INR119, designed as an inhibitor of MEK1/2, will enhance the activity of its fission yeast homologue, Wis1, under oxidative stress. To investigate the generality of these findings, we now study the effect of INR119 in human cells under similar conditions. Cells of the established breast cancer line MCF-7 were exposed to H2O2...
Source
#1Yuxiang Song (JLU: Jilin University)H-Index: 8
#2Juan J. Loor (UIUC: University of Illinois at Urbana–Champaign)H-Index: 68
Last. Xinwei Li (JLU: Jilin University)H-Index: 23
view all 12 authors...
ABSTRACT Ketosis is a common metabolic disorder in high-producing dairy cows during the peripartal period. Negative energy balance leads to increased circulating levels of nonesterified fatty acids (NEFA) and β-hydroxybutyrate (BHB), consequently increasing the risk of ketosis. It is well-known that NEFA and BHB can induce lipotoxicity and oxidative stress in bovine tissues/organs including the liver and adipose tissue. Although the mammary gland is one important site for NEFA and BHB metabolism...
2 CitationsSource
#1Xudong SunH-Index: 7
#2Yan TangH-Index: 1
Last. Chuang XuH-Index: 7
view all 12 authors...
ABSTRACT Ketosis is a serious metabolic disorder characterized by systemic and hepatic oxidative stress, inflammation, and apoptosis, as well as reduced milk yield. Because of the paucity of data on mammary responses during ketosis, the aim of this study was to evaluate alterations in oxidative stress, NF-κB signaling, NLRP3 inflammasome, and caspase apoptotic pathways in mammary gland of dairy cows with ketosis. Blood, mammary gland tissue, and milk samples were collected from healthy cows [Con...
1 CitationsSource
#1Serdal KurtH-Index: 2
#2Funda EşkiH-Index: 2
Last. Ayhan BaştanH-Index: 4
view all 5 authors...
Aim of this study was to investigate the effect of heat stress on total oxidant capacity (TOC) in hair goats grown at different altitudes in the same season. The study was carried out on 208 hair goats (25 male and 183 female) in 11 different districts of Adana province (Turkey) in the summer season. The districts were grouped as 0-99 m (Grop 1), 100-500 m (Group 2) and higher than 500 m (Group 3) according to altitude characteristics, and goats were classified into two groups as under 3 years a...
2 CitationsSource
#1Yuxiang Song (JLU: Jilin University)H-Index: 8
#2Juan J. Loor (UIUC: University of Illinois at Urbana–Champaign)H-Index: 68
Last. Xinwei Li (JLU: Jilin University)H-Index: 23
view all 9 authors...
Left displaced abomasum (LDA) occurs at high frequency in the early postpartum period and can affect production performance of dairy cows. Clinical diagnosis of LDA is usually done by abdominal auscultation and percussion. The purpose of this study was to explore the potential applicability of blood biomarkers for early warning and diagnosis of LDA in dairy cows. Twenty early postpartum healthy cows and thirty early postpartum LDA cows of similar parity were used. A receiver operating characteri...
Source