Digoxin Suppresses Pyruvate Kinase M2-Promoted HIF-1α Transactivation in Steatohepatitis

Ouyang, Xinshou; Han, Sheng Na; Zhang, Ji Yuan; Dioletis, Evangelos; Németh, Balázs Tamás; Pacher, Pál; Feng, Dechun; Bataller, Ramón; Cabezas, Joaquín; Stärkel, Peter; Caballería, Joan; Pongratz, Rebecca L.; Cai, Shi Ying; Schnabl, Bernd; Hoque, Rafaz; Chen, Yonglin; Wei, Yang; García-Martínez, Irma; Wang, Fu Sheng; Gao, Bin; Török, Natalie J.; Kibbey, Richard G.; Mehal, Wajahat Z.

doi:10.1016/j.cmet.2018.04.007

Cited by 31 publications

(44 citation statements)

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“…From the above results, there is significant positive correlation between levels of GSH, GPx activity, and VNS; similarly, there is an inverse correlation between levels of GSSG and VNS. Consistent with these results, several studies have documented that there is a link between oxidative stress and diverse liver diseases [46,47]. Therefore, the VNS reversal of the observed liver injuries induced by IRI in our study further supports the hypothesis that hepatic protection by VNS operates mainly via activation of glutathione metabolism.…”

Section: Discussionsupporting

confidence: 92%

Vagus Nerve Stimulation Alleviates Hepatic Ischemia and Reperfusion Injury by Regulating Glutathione Production and Transformation

Xia

Liu

Liang

et al. 2020

Oxidative Medicine and Cellular Longevity

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Inflammation and oxidative stress are pivotal mechanisms for the pathogenesis of ischemia and reperfusion injury (IRI). Vagus nerve stimulation (VNS) may participate in maintaining oxidative homeostasis and response to external stimulus or injury. We investigated whether the in vivo VNS can protect the liver from IRI. In this study, hepatic IRI were induced by ligating the vessels supplying the left and middle lobes of the liver, which underwent 1 h occlusion followed with 24 h reperfusion. VNS was initiated 15 min after ischemia and continued 30 min. Hepatic function, histology, and apoptosis rates were evaluated after 24 h reperfusion. Compared with the IRI group, VNS significantly improved hepatic function. The protective effect was accompanied by a reduction in histological damage in the ischemic area, and the apoptosis rate of hepatocytes has considerable reduction. To find the underlying mechanism, proteomic analysis was performed and differential expression of glutathione synthetase (GSS) and glutathione S-transferase (GST) was observed. Subsequently, test results indicated that VNS upregulated the expression of mRNA and protein of GSS and GST. Meanwhile, VNS increased the plasma levels of glutathione and glutathione peroxidases. We found that VNS alleviated hepatic IRI by upregulating the antioxidant glutathione via the GSS/glutathione/GST signaling pathway.

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Section: Discussionsupporting

confidence: 92%

Vagus Nerve Stimulation Alleviates Hepatic Ischemia and Reperfusion Injury by Regulating Glutathione Production and Transformation

Xia

Liu

Liang

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…Moreover, the biological effects of PKM2 in immune cells appears to be largely mediated by nuclear effects (e.g., via HIF-1α or β-catenin), while we found no evidence of a nuclear role of PKM2 in ECs. PKM2 has also been proposed to play a role in hepatocyte steatosis, again via modulation of HIF-1α (30), and in kidney podocytes and diabetic glomerulonephropathy via nuclear mechanism (31). Both of these cell types are highly oxidative, in contrast to ECs.…”

Section: Resultsmentioning

confidence: 99%

Endothelial pyruvate kinase M2 maintains vascular integrity

Kim¹,

Jang²,

Dharaneeswaran³

et al. 2018

Journal of Clinical Investigation

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The M2 isoform of pyruvate kinase (PKM2) is highly expressed in most cancer cells, and has been studied extensively as a driver of oncogenic metabolism. In contrast, the role of PKM2 in nontransformed cells is little studied, and nearly nothing is known of its role, if any, in quiescent cells. We show here that endothelial cells express PKM2 almost exclusively over PKM1. In proliferating endothelial cells, PKM2 is required to suppress p53 and maintain cell cycle progression. In sharp contrast, PKM2 has a strikingly different role in quiescent endothelial cells, where inhibition of PKM2 leads to degeneration of tight junctions and barrier function. Mechanistically, PKM2 regulates barrier function independently of its canonical activity as a pyruvate kinase. Instead, PKM2 suppresses NF-kB and its downstream target, the vascular permeability factor angiopoietin 2. As a consequence, loss of endothelial cell PKM2 in vivo predisposes mice to VEGF-induced vascular leak, and to severe bacteremia and death in response to sepsis. Together, these data demonstrate new roles of PKM2 in quiescent cells, and highlight the need for caution in developing cancer therapies that target PKM2.

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“…Even with these reports, there are still gaps in our knowledge on NILD. For example, hepatocytic apoptosis, oxidative stress, fibrosis or steatosis characterizes liver damage in ASH/NASH, aging or HCV infection, which has been regarded as the early hint of cirrhosis or even hepatocellular carcinoma. But it is still unclear whether the noise can elicit these manifestations or not.…”

Section: Discussionmentioning

confidence: 99%

Acid sphingomyelinase mediates the noise‐induced liver disorder in mice

Meng

Xie

et al. 2019

Clin Exp Pharma Physio

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Summary Noise‐induced structural and functional disorder of the liver has been realized, but the underlying mechanism remains to be characterized, which has limited the introduction of precautious measures. Over‐activation of acid sphingomyelinase (ASM)/ceramide (Cer) pathway takes centre stage in hepatocyte injury entailed by various stimulus. We aimed to investigate whether it mediated the noise elicited liver disorder on infrastructure, lipid metabolism, apoptosis, and oxidative stress. Mice were exposed to broad band noise (20–20k Hz, 90–110 dB) for 1, 3, 5 or 7 days by 3 hr/d. Doxepin hydrochloride (DOX), an ASM inhibitor was given by 5 mg/kg/d gavage. We showed that 5 or 7 days intense, broad band noise exposure caused significant infrastructure derangement and lipid droplets storage in hepatocytes. The content of cholesterol, free fatty acids or triglyceride was increased significantly in liver tissue upon noise stimulation. Moreover, the noise promoted apoptosis and superoxide generation in hepatocytes significantly, enhancing activity of aspartate aminotransferase (AST) or alanine amino transferase (ALT) in serum. Acid sphingomyelinase activity and Cer generation in liver tissue were elevated by noise exposure, which was normalized with DOX administrated. Accordingly, DOX alleviated steatosis, apoptosis, oxidative stress and enzymatic change in hepatocytes or serum of noise exposed mice substantially. In summary, our results suggest the ASM/Cer pathway contributes to the broad band noise elicited liver damage in mice.

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Digoxin Suppresses Pyruvate Kinase M2-Promoted HIF-1α Transactivation in Steatohepatitis

Cited by 31 publications

References 0 publications

Vagus Nerve Stimulation Alleviates Hepatic Ischemia and Reperfusion Injury by Regulating Glutathione Production and Transformation

Vagus Nerve Stimulation Alleviates Hepatic Ischemia and Reperfusion Injury by Regulating Glutathione Production and Transformation

Endothelial pyruvate kinase M2 maintains vascular integrity

Acid sphingomyelinase mediates the noise‐induced liver disorder in mice

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