Augmenter of liver regeneration promotes mitochondrial biogenesis in renal ischemia–reperfusion injury

Huang, Lili; Long, Rui-Ting; Jiang, Gui-Ping; Jiang, Xiao; Sun, Hang; Guo, Hui; Liao, Xiaohui

doi:10.1007/s10495-018-1487-2

Cited by 15 publications

(15 citation statements)

References 36 publications

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“…Pathological alterations in mitochondrial structure and function have been observed in renal tubular cells in various experimental models of AKI (Parikh et al, 2015;Kezic et al, 2016;Yu and Lee, 2016). In this study, we established an in vitro I/R model with glucose-free culture medium and hypoxia reoxygenation according to previous studies (Jiang et al, 2010;Dong et al, 2015;Zhang et al, 2015;Huang et al, 2018). The changes in LC3-II during I/R was associated with a marked reduction in TIMM23 and TOMM20, indicating activation of mitochondrial clearance.…”

Section: Discussionmentioning

confidence: 84%

“…Intraperitoneal injection of exogenous recombinant ALR enhances the proliferation of renal tubular cells and prevents tubular cell apoptosis (Liao et al, 2010). Furthermore, we found that the knockdown of ALR suppresses mitochondrial biogenesis in I/R injury in vitro (Huang et al, 2018). However, if and how ALR participates in the mitophagy pathway of apoptosis in AKI remains unknown, although mitochondria deficiencies are closely associated with apoptosis.…”

Section: Introductionmentioning

confidence: 84%

“…In the present study, we used human kidney proximal tubular (HK-2) cells to establish an I/R model in vitro (Huang et al, 2018;Tang et al, 2018), and ALR was knocked down in HK-2 cells by infection with short hairpin RNA (shRNA) lentiviral particles to investigate the effects of ALR on cell apoptosis, mitochondrial dysfunction, and PINK1/Parkinmediated mitophagy during I/R injury.…”

Section: Introductionmentioning

confidence: 99%

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Augmenter of Liver Regeneration Protects Renal Tubular Epithelial Cells From Ischemia-Reperfusion Injury by Promoting PINK1/Parkin-Mediated Mitophagy

et al. 2020

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Ischemia-reperfusion (I/R) is the most common cause of acute kidney injury (AKI) and can induce apoptosis in renal epithelial tubule cells. Mitochondrial dysfunction is one of the main reasons for I/R-induced apoptosis. Accumulating evidence suggests that PINK1/Parkin-mediated mitophagy possibly plays a renoprotective role in kidney disease by removing impaired mitochondria and preserving a healthy population of mitochondria. Our previous study showed that augmenter of liver regeneration (ALR) alleviates tubular epithelial cells apoptosis in rats with AKI, although the specific mechanism remains unclear. In this study, we investigated the role of ALR in I/Rinduced mitochondrial pathway of apoptosis. We knocked down ALR with short hairpin RNA lentiviral and established an I/R model in human kidney proximal tubular (HK-2) cells in vitro. We observed that the knockdown of ALR aggravated mitochondrial dysfunction and increased the mitochondrial reactive oxygen species (ROS) levels, leading to an increase in cell apoptosis via inhibition of mitophagy. We also found that the PINK1/Parkin pathway was activated by I/R via confocal microscopy and Western blot. Furthermore, the knockdown of ALR suppressed the activation of PINK1 and Parkin. These findings collectively indicate that ALR may protect HK-2 cells from I/R injury by promoting mitophagy, and the mechanism by which ALR regulates mitophagy seems to be related to PINK1 and Parkin. Consequently, ALR may be used as a potential therapeutic agent for AKI in the future.

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Section: Discussionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

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Augmenter of Liver Regeneration Protects Renal Tubular Epithelial Cells From Ischemia-Reperfusion Injury by Promoting PINK1/Parkin-Mediated Mitophagy

et al. 2020

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“…It was shown that ALR plays an important role in the proliferation of hepatocytes . ALR was shown to play an important role in the maintenance of mitochondria and mitochondrial biogenesis . Recently, Pu et al .…”

Section: Introductionmentioning

confidence: 99%

“…2 ALR was shown to play an important role in the maintenance of mitochondria and mitochondrial biogenesis. 2,3 Recently, Pu et al had shown that ALR regulated autophagy in renal ischemia-reperfusion injury through the adenosine monophosphate-activated protein kinase/mammalian target of rapamycin pathway. 4 It was shown that liverspecific deletion of ALR resulted in hepatic necrosis, inflammation, and liver fibrosis of mice at 4-8 weeks after birth.…”

Section: Introductionmentioning

confidence: 99%

Augmenter of liver regeneration enhances cell proliferation through the microRNA‐26a/Akt/cyclin D1 pathway in hepatic cells

Gupta

Sata

Ahamad

et al. 2019

Hepatology Research

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Aim Hepatocytes can proliferate and regenerate when injured by toxins, viral infections, and so on. Augmenter of liver regeneration (ALR) is a key regulator of liver regeneration, but the mechanism is unknown. The role of ALR in other cell types is not known. In the present study, we investigated the relationship between microRNA (miRNA)‐26a and ALR in the Huh7 cell line and adipose tissue‐derived mesenchymal cells from chronic liver disease patients and healthy individuals. Methods Huh7 cells were transfected independently with ALR and miRNA‐26a expression vectors, and their effects on cell proliferation, the expression of miRNA‐26a, and activation of the phosphatase and tensin homolog and Akt signaling pathways were determined. The experiments were repeated on mesenchymal stem cells derived from healthy individuals and chronic liver disease patients to see whether the observations can be replicated in primary cells. Results Overexpression of ALR or miRNA‐26a resulted in an increase of the phosphorylation of Akt and cyclin D1 expression, whereas it resulted in decreased levels of p‐GSK‐3β and phosphatase and tensin homolog in Huh7 cells. The inhibition of ALR expression by ALR siRNA or anti‐miR‐26a decreased the Akt/cyclin D1 signaling pathway, leading to decreased proliferation. Mesenchymal stem cells isolated from the chronic liver disease patients had a higher ALR expression, while the mesenchymal stem cells isolated from healthy volunteers responded to the growth factor treatments for increased ALR expression. It was found that there was a significant increase in miRNA‐26a expression and proliferation. Conclusions These data clearly showed that ALR induced the expression of miRNA‐26a, which downregulated phosphatase and tensin homolog, resulting in an increased p‐Akt/cyclin D1 pathway and enhanced proliferation in hepatic cells.

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Lack of Augmenter of Liver Regeneration Disrupts Cholesterol Homeostasis of Liver in Mice by Inhibiting the AMPK Pathway

Wang¹,

Liu²,

Gai³

et al. 2020

Hepatol Commun

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It is well known that excessive cholesterol accumulation within hepatocytes deteriorates nonalcoholic fatty liver disease (NAFLD). Augmenter of liver regeneration (ALR) has been reported to alleviate NAFLD through anti‐apoptosis; however, whether ALR could protect liver from cholesterol‐induced NAFLD remains unclear. Mice with heterozygous deletion of Gfer (the gene for ALR, Gfer +/− ) were generated, and liver steatosis was induced by either choline‐deficient ethionine‐supplemented, methionine choline–deficient diet for 4 weeks, or high‐fat diet for 16 weeks. The results showed that Gfer +/− mice developed a more severe fatty liver phenotype than Gfer +/+ mice. The livers of Gfer +/− mice exhibited a higher concentration of cholesterol and low‐density lipoprotein compared with the normal mice. Transcriptome‐based analysis predicts low‐density lipoprotein receptor (LDLR) primarily involved in the metabolic pathway. The experiments further indicate that cholesterol accumulation within hepatocytes is closely associated with enhancing the expression of LDLR and activation of sterol regulatory element binding protein 2 (SREBP2). Because adenosine monophosphate–activated protein kinase (AMPK) is a critical regulator of SREBP2 activation, we measured whether the activity of AMPK was regulated by ALR. We found that knockdown of ALR expression inhibited the phosphorylation of LKB1, an upstream activator of AMPK, followed by AMPK inactivation and SREBP2 maturation/nuclear translocation, leading to extensive cholesterol accumulation. Meanwhile, cellular oxidative stress increased as a result of ALR knockdown, indicating that ALR might also have a role in suppressing reactive oxygen species production. Conclusion : Our results confirm that ALR regulates cholesterol metabolism and alleviates hepatic steatosis probably through the LKB1‐AMPK‐SREBP2‐LDLR pathway in vivo and in vitro , providing a putative mechanism for combating fatty liver disease.

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Augmenter of liver regeneration promotes mitochondrial biogenesis in renal ischemia–reperfusion injury

Cited by 15 publications

References 36 publications

Augmenter of Liver Regeneration Protects Renal Tubular Epithelial Cells From Ischemia-Reperfusion Injury by Promoting PINK1/Parkin-Mediated Mitophagy

Augmenter of Liver Regeneration Protects Renal Tubular Epithelial Cells From Ischemia-Reperfusion Injury by Promoting PINK1/Parkin-Mediated Mitophagy

Augmenter of liver regeneration enhances cell proliferation through the microRNA‐26a/Akt/cyclin D1 pathway in hepatic cells

Lack of Augmenter of Liver Regeneration Disrupts Cholesterol Homeostasis of Liver in Mice by Inhibiting the AMPK Pathway

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