Indomethacin suppresses LAMP-2 expression and induces lipophagy and lipoapoptosis in rat enterocytes via the ER stress pathway

Narabayashi, Ken; Ito, Yuko; Eid, Nabil; Maemura, Kentaro; Inoue, Takuya; Takeuchi, Toshihisa; Otsuki, Yoshinori; Higuchi, Kazuhide

doi:10.1007/s00535-014-0995-2

Cited by 34 publications

(38 citation statements)

References 67 publications

(150 reference statements)

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“…This special type of selective autophagy is referred to as "lipophagy" [35] . Its major mechanism occurs after the fusion of autophagosomes and lysosomes when CEs in LDs are hydrolyzed by specific enzymes into free cholesterols, which can transfer through the cell membrane and then be carried by apoA-I or HDL in back to the liver [36,37] .…”

Section: Effects Of Macrophage Autophagy On Cholesterol Effluxmentioning

confidence: 99%

The roles of macrophage autophagy in atherosclerosis

Shao

Han

Zeng³

et al. 2016

Acta Pharmacol Sin

184

116

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Although various types of drugs and therapies are available to treat atherosclerosis, it remains a major cause of mortality throughout the world. Macrophages are the major source of foam cells, which are hallmarks of atherosclerotic lesions. Consequently, the roles of macrophages in the pathophysiology of atherosclerosis are increasingly investigated. Autophagy is a self-protecting cellular catabolic pathway. Since its discovery, autophagy has been found to be associated with a variety of diseases, including cardiovascular diseases, malignant tumors, neurodegenerative diseases, and immune system disorders. Accumulating evidence demonstrates that autophagy plays an important role in inhibiting inflammation and apoptosis, and in promoting efferocytosis and cholesterol efflux. These facts suggest the induction of autophagy may be exploited as a potential strategy for the treatment of atherosclerosis. In this review we mainly discuss the relationship between macrophage autophagy and atherosclerosis and the molecular mechanisms, as well as the recent advances in targeting the process of autophagy to treat atherosclerosis.

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Section: Effects Of Macrophage Autophagy On Cholesterol Effluxmentioning

confidence: 99%

The roles of macrophage autophagy in atherosclerosis

Shao

Han

Zeng³

et al. 2016

Acta Pharmacol Sin

184

116

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“…In a previous study, Narabayashi et al (2015) reported that IM induced accumulation of cytoplasmic lipid droplets (LDs), and lipophagy (autophagic degradation of portions of LDs or whole LDs either alone or mixed with other cell contents) was promoted to remove the toxic LDs in IEC6 cells. To examine how autophagy (including lipophagy) is involved in IMinduced intestinal epithelial injury, we used Atg5-CKO mice in which autophagy did not occur only in intestinal epithelial cells.…”

Section: Evaluation Of Intestinal Epithelial Injury In Wt Andmentioning

confidence: 99%

“…Since autophagy is reported to take place after IM treatment as well as apoptosis in IEC6 cells (Narabayashi et al, 2015), we focused on autophagy and examined the role of autophagy in intestinal epithelial damage. Here, we showed that prevention of autophagy reduced apoptosis-mediated, IM-induced intestinal epithelial cell damage.…”

Section: Amelioration Of Indomethacin-induced Injury By Autophagy Defmentioning

confidence: 99%

Autophagy Deficiency Diminishes Indomethacin-Induced Intestinal Epithelial Cell Damage through Activation of the ERK/Nrf2/HO-1 Pathway

Harada

Nakagawa

Yokoe

et al. 2015

J Pharmacol Exp Ther

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Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause epithelial cell damage in the stomach, intestine, and colon. NSAIDs are reported to induce autophagy and apoptosis in intestinal epithelial cells; however, their role in cell damage is poorly understood. To examine the role of autophagy in cell damage, we used autophagy-related gene Atg5-conditional knockout mice, in which the Atg5 gene is only knocked out in intestinal epithelial cells. In an indomethacin (IM)-induced gastrointestinal ulcer mouse model, intestinal epithelium damage was reduced in Atg5-conditional knockout mice compared with wild-type mice. IM-induced damage in IEC6 rat intestinal epithelial cells was reduced when Atg5 was silenced (IEC6shAtg5 cells). Western blot analyses indicated that IM-induced apoptosis decreased, and the potent, oxidative stress-related extracellular signal-regulated kinase (ERK)/nuclear factor-erythroid2-like2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway was upregulated in IEC6shAtg5 cells. An experiment using a reactive oxygen species (ROS)-sensitive fluorescent dye in IEC6shAtg5 cells revealed that the amount of ROS at the baseline and the rate of increase after IM treatment were lower than in intact IEC6 cells. The mitochondrial membrane potential at the baseline and the reduction rate in IM-treated IEC6shAtg5 cells were lower than in intact IEC6 cells, indicating that autophagy deficiency increased ROS production caused by mitochondrial disturbance. Furthermore, MnTMPyP, a manganese-superoxide dismutase mimetic, significantly inhibited IM-induced autophagy and subsequent apoptosis as well as activation of the ERK/Nrf2/HO-1 pathway. These data suggest that autophagy deficiency and subsequent activation of the ERK/Nrf2/HO-1 pathway diminished IM-induced, apoptosis-mediated intestinal epithelial cell damage, and genetic analyses of single nucleotide polymorphisms in autophagyrelated genes could predict NSAID-induced intestinal injury.

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“…ER stress was also observed in cultured rat enterocytes treated with indomethacin (Narabayashi et al. 2015). …”

Section: Introductionmentioning

confidence: 99%

Role of endoplasmic reticulum stress in drug‐induced toxicity

Foufelle

Fromenty

2016

Pharmacology Res & Perspec

188

161

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Drug‐induced toxicity is a key issue for public health because some side effects can be severe and life‐threatening. These adverse effects can also be a major concern for the pharmaceutical companies since significant toxicity can lead to the interruption of clinical trials, or the withdrawal of the incriminated drugs from the market. Recent studies suggested that endoplasmic reticulum (ER) stress could be an important event involved in drug liability, in addition to other key mechanisms such as mitochondrial dysfunction and oxidative stress. Indeed, drug‐induced ER stress could lead to several deleterious effects within cells and tissues including accumulation of lipids, cell death, cytolysis, and inflammation. After recalling important information regarding drug‐induced adverse reactions and ER stress in diverse pathophysiological situations, this review summarizes the main data pertaining to drug‐induced ER stress and its potential involvement in different adverse effects. Drugs presented in this review are for instance acetaminophen (APAP), arsenic trioxide and other anticancer drugs, diclofenac, and different antiretroviral compounds. We also included data on tunicamycin (an antibiotic not used in human medicine because of its toxicity) and thapsigargin (a toxic compound of the Mediterranean plant Thapsia garganica) since both molecules are commonly used as prototypical toxins to induce ER stress in cellular and animal models.

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Indomethacin suppresses LAMP-2 expression and induces lipophagy and lipoapoptosis in rat enterocytes via the ER stress pathway

Cited by 34 publications

References 67 publications

The roles of macrophage autophagy in atherosclerosis

The roles of macrophage autophagy in atherosclerosis

Autophagy Deficiency Diminishes Indomethacin-Induced Intestinal Epithelial Cell Damage through Activation of the ERK/Nrf2/HO-1 Pathway

Role of endoplasmic reticulum stress in drug‐induced toxicity

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