Palmitate Induces ER Stress and Autophagy in H9c2 Cells: Implications for Apoptosis and Adiponectin Resistance

Park, Min; Sabetski, Anna; Chan, Yee Kwan; Turdi, Subat; Sweeney, Gary

doi:10.1002/jcp.24781

Cited by 72 publications

(56 citation statements)

References 55 publications

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“…Although Wei et al reported that U0126, an inhibitor of extracellular signal-regulated kinase (ERK), reduced PA-induced apoptosis through partial suppression of intracellular ROS generation, there was no direct evidence to prove the involvement of ROS [4]. A recent study demonstrated that autophagy was induced by PA as an adaptive response to ER stress since it was sensitive to ER stress inhibition in H9c2 cells [9], however, whether ROS plays a role in PA-induced autophagy and apoptosis remains unknown.…”

Section: Introductionmentioning

confidence: 95%

Palmitate promotes autophagy and apoptosis through ROS-dependent JNK and p38 MAPK

Liu

Chang

et al. 2015

Biochemical and Biophysical Research Communications

135

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Section: Introductionmentioning

confidence: 95%

Palmitate promotes autophagy and apoptosis through ROS-dependent JNK and p38 MAPK

Liu

Chang

et al. 2015

Biochemical and Biophysical Research Communications

135

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“…Is AMPK/mTOR-dependent or -independent, RespectivelyRecent studies have shown that the cytotoxic effects of fatty acids and nutrient starvation can induce autophagy (51)(52)(53)(54). However, it is not known whether the two different stresses induce autophagy in the same manner.…”

Section: Autophagy Induced By Nutrient Starvation or Lipotoxicitymentioning

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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“…Our data indicate that at least two of the three major UPR signaling pathways, IRE1/XBP1 and PERK/CHOP were altered by PA. It has been suggested that ER stress is involved in PA-induced apoptosis [12,19,20,31]. Based on the data that blocking ER stress inhibited PA-induced apoptosis in SMMC-7721 cells, we suggest that ER stress promotes PA-induced apoptosis in hepatocyte.…”

Section: Discussionmentioning

confidence: 65%

“…It has been reported that PA can initiate ER stress response in various cell types [29][30][31][32]. We firstly detected the potential role of PA in the induction of ER stress in SMMC-7721 cells.…”

Section: Discussionmentioning

confidence: 98%

Differential Activation of ER Stress Signal Pathways Contributes to Palmitate-Induced Hepatocyte Lipoapoptosis

Zhao¹,

Yao²,

Cheng³

et al. 2016

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Saturated free fatty acids-induced hepatocyte lipoapoptosis plays a pivotal role in non-alcoholic steatohepatitis. The activation of endoplasmic reticulum (ER) stress is involved in hepatocyte lipoapoptosis induced by the saturated free fatty acid palmitate (PA). However, the underlying mechanisms of the role of ER stress in hepatocyte lipoapoptosis remain largely unclear. In this study, we showed that PA and tunicamycin (Tun), a classic ER stress inducer, resulted in differential activation of ER stress pathways. Our data revealed that PA induced chronic and persistent ER stress response, but Tun induced acute and transient ER stress response. Compared with Tun treatment, PA induced much lower glucose-regulated protein 78 (GRP78), a central regulator of ER homeostasis, accumulation. It is noteworthy that GRP78 over-expression not only inhibited PA-induced ER stress but also decreased PA-induced apoptosis. Taken together, our data suggest that the differential activation of ER stress signal plays an important role in PA-induced hepatocyte lipoapoptosis. More detailed studies on the mechanisms of PA in repressing the accumulation of GRP78 will contribute to the understanding of molecular mechanisms of lipoapoptosis.

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Palmitate Induces ER Stress and Autophagy in H9c2 Cells: Implications for Apoptosis and Adiponectin Resistance

Cited by 72 publications

References 55 publications

Palmitate promotes autophagy and apoptosis through ROS-dependent JNK and p38 MAPK

Palmitate promotes autophagy and apoptosis through ROS-dependent JNK and p38 MAPK

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

Differential Activation of ER Stress Signal Pathways Contributes to Palmitate-Induced Hepatocyte Lipoapoptosis

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