Microsomal prostaglandin E synthase 2 deficiency is resistant to acetaminophen-induced liver injury

Wang, Hu; Zhang, Rumeng; Zhu, Yangyang; Teng, Tian; Cheng, Yun; Chowdhury, Apu; Lü, Jing; Song, Jun; Yin, Xiaoxing; Sun, Ying

doi:10.1007/s00204-019-02543-1

Cited by 10 publications

(6 citation statements)

References 33 publications

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“…In previous studies, we reported that mPGES-2 deletion antagonizes acetaminophen-induced liver injury and enhances streptozotocin (STZ)-induced liver toxicity via GLUT2-mediated STZ uptake. [17,50] However, the effect of mPGES-2 deficiency on fatty liver disease and lipid metabolism is unclear. In the present study, we used whole-body mPGES-2 KO mice fed either an HFD or an MCD diet.…”

Section: Discussionmentioning

confidence: 99%

“…Our group is currently investigating the role of mPGES‐2 in different metabolic diseases, particularly diabetes and liver disorders. In previous studies, we reported that mPGES‐2 deletion antagonizes acetaminophen‐induced liver injury and enhances streptozotocin (STZ)‐induced liver toxicity via GLUT2‐mediated STZ uptake 17,50. However, the effect of mPGES‐2 deficiency on fatty liver disease and lipid metabolism is unclear.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of mPGES‐2 ameliorates NASH by activating NR1D1 via heme

Zhong

Cai

et al. 2022

Hepatology

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Background and Aims: Nonalcoholic fatty liver disease (NAFLD), a complex metabolic syndrome, has limited therapeutic options. Microsomal prostaglandin E synthase-2 (mPGES-2) was originally discovered as a prostaglandin E 2 (PGE 2 ) synthase; however, it does not produce PGE 2 in the liver. Moreover, the role of mPGES-2 in NAFLD remains undefined. Herein, we aimed to determine the function and mechanism of mPGES-2 in liver steatosis and steatohepatitis. Approach and Results: To evaluate the role of mPGES-2 in NAFLD, wholebody or hepatocyte-specific mPGES-2-deficient mice fed a high-fat or methionine-choline-deficient diet were used. Compared with control mice, mPGES-2-deficient mice showed reduced hepatic lipid accumulation, along with ameliorated liver injury, inflammation, and fibrosis. Furthermore, the protective effect of mPGES-2 deficiency against NAFLD was dependent on decreased cytochrome P450 4A14 and increased acyl-CoA thioesterase 4 levels regulated by the heme receptor nuclear receptor subfamily 1 group D member 1 (NR1D1), but not PGE 2 . Heme regulated the increased NR1D1 activity mediated by mPGES-2 deficiency. Further, we confirmed the protective role of the mPGES-2 inhibitor SZ0232 in NAFLD therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inhibition of mPGES‐2 ameliorates NASH by activating NR1D1 via heme

Zhong

Cai

et al. 2022

Hepatology

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“…As an essential detoxification factor, GSH can affect the onset and recovery of APAP-induced liver injury. 44 SIRT6 plays a critical role in redox signaling in the liver, and its downregulation is closely related to enhanced oxidative stress via excessive ROS generation, 16 , 19 implying that the maintenance of normal SIRT6 levels is important to reduce APAP-induced liver damage. Similar to the report by Kim et al, 19 we found that hepatocyte SIRT6-deficient mice showed low levels of GSH, which is relevant to the reduced mRNA levels of Gclc, Gclm , and Sod2 , which encode GSH synthesis enzymes.…”

Section: Discussionmentioning

confidence: 99%

Hepatic SIRT6 Modulates Transcriptional Activities of FXR to Alleviate Acetaminophen-induced Hepatotoxicity

Liu

Pan

et al. 2022

Cellular and Molecular Gastroenterology and Hepatology

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“…RNA isolation and cDNA preparation were performed as described previously 21 , 22 . We measured the expression of 18S for normalization, as previously described 21 .…”

Section: Methodsmentioning

confidence: 99%

Simultaneous silencing Aurora-A and UHRF1 inhibits colorectal cancer cell growth through regulating expression of DNMT1 and STAT1

Han

Chen

et al. 2021

Int. J. Med. Sci.

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Aurora-A has attracted a great deal of interest as a potential therapeutic target for patients with CRC. However, the outcomes of inhibitors targeting Aurora-A are not as favorable as expected, and the basis behind the ineffectiveness remains unknown. Here, we found that signal transducer and activator of transcription 1 (STAT1) was highly expressed in colorectal cancer (CRC) xenograft mouse models that were resistant to alisertib, an Aurora-A inhibitor. Unexpectedly, we found that alisertib disrupted Aurora-A binding with ubiquitin-like with plant homeodomain and ring finger domain 1 (UHRF1), leading to UHRF1 mediated ubiquitination and degradation of DNA methyltransferase 1 (DNMT1), which in turn resulted in demethylation of CpG islands of STAT1 promoter and STAT1 overexpression. Simultaneous silencing Aurora-A and UHRF1 prevented STAT1 overexpression and effectively inhibited CRC growth. Hence, concomitant targeting Aurora-A and UHRF1 can be a promising therapeutic strategy for CRC.

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Microsomal prostaglandin E synthase 2 deficiency is resistant to acetaminophen-induced liver injury

Cited by 10 publications

References 33 publications

Inhibition of mPGES‐2 ameliorates NASH by activating NR1D1 via heme

Inhibition of mPGES‐2 ameliorates NASH by activating NR1D1 via heme

Hepatic SIRT6 Modulates Transcriptional Activities of FXR to Alleviate Acetaminophen-induced Hepatotoxicity

Simultaneous silencing Aurora-A and UHRF1 inhibits colorectal cancer cell growth through regulating expression of DNMT1 and STAT1

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