Protein arginine methyl transferase 1– and Jumonji C domain‐containing protein 6–dependent arginine methylation regulate hepatocyte nuclear factor 4 alpha expression and hepatocyte proliferation in mice

Zhao, Jie; Adams, Abby; Roberts, Ben; O’Neil, Maura; Vittal, Anusha; Schmitt, Timothy M.; Kumer, Sean C.; Cox, Josiah; Li, Zhuan; Weinman, Steven A.; Tikhanovich, Irina

doi:10.1002/hep.29587

Cited by 51 publications

(55 citation statements)

References 41 publications

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“…To generate liver‐specific mGPDH‐deficient mice, mGPDH flox/flox or mGPDH flox/wt mice were transduced with hepatocyte‐specific adeno‐associated viral 8 (AAV8)‐thyroxine‐binding globulin (TBG)‐cre (2 × 10 11 v.g. ), and AAV8‐TBG‐GFP served as the control . To induce acute ER stress, mice were injected intraperitoneally with tunicamycin (TM; Abcam) at 1 mg/kg body weight.…”

Section: Methodsmentioning

confidence: 99%

Deficiency of Mitochondrial Glycerol 3‐Phosphate Dehydrogenase Contributes to Hepatic Steatosis

Zheng

Xiong

et al. 2019

Hepatology

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Mitochondrial glycerol 3‐phosphate dehydrogenase (mGPDH) is an integral component of the respiratory chain, and recent studies have suggested that it plays an important role in hepatic glucose homeostasis. However, its function in hepatic lipid metabolism is unclear. Here, we identified a role for mGPDH in nonalcoholic fatty liver disease (NAFLD). Specifically, mGPDH expression and activity were lower in fatty livers from patients and mice with NAFLD (ob/ob, high‐fat diet [HFD] and db/db). Liver‐specific depletion of mGPDH in mice or mGPDH knockdown in cultured hepatocytes exacerbated diet‐induced triglyceride accumulation and steatosis through enhanced lipogenesis. RNA‐sequencing revealed that mGPDH regulated endoplasmic reticulum (ER)‐related proteins and processes. mGPDH deletion exacerbated tunicamycin (ER stress inducer)‐induced hepatic steatosis, whereas tauroursodeoxycholic acid (ER stress inhibitor) rescued mGPDH depletion–induced steatosis on an HFD. Moreover, ER stress induced by mGPDH depletion could be abrogated by the intracellular Ca2+ chelator 1,2‐bis (2‐aminophenoxy) ethane N,N,N´,N´‐tetraacetic acid acetoxymethyl ester, mitochondrial permeability transition pore (mPTP) inhibitor cyclosporine A, or cyclophilin‐D (Cyp‐D) knockdown. mGPDH promoting Cyp‐D ubiquitination was also observed. Finally, liver‐specific mGPDH overexpression attenuated hepatic steatosis in ob/ob and HFD mice. Conclusion: mGPDH is a pivotal regulator of hepatic lipid metabolism. Its deficiency induces ER stress by suppressing Cyp‐D ubiquitination, a key regulator of the mitochondrial Ca2+ conductance channel mPTP, and results in hepatic steatosis. mGPDH may be a potential therapeutic target for the treatment of NAFLD.

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Section: Methodsmentioning

confidence: 99%

Deficiency of Mitochondrial Glycerol 3‐Phosphate Dehydrogenase Contributes to Hepatic Steatosis

Zheng

Xiong

et al. 2019

Hepatology

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“…PRMT1 regulates multiple aspects of liver biology, including cell proliferation, ( 19 ) fatty acid metabolism, ( 35 ) glucose metabolism, ( 36 ) innate immune response, ( 37 ) oxidative stress response, and apoptosis. ( 38 ) However, it role in liver cancer development is controversial.…”

Section: Discussionmentioning

confidence: 99%

“…Immunostaining on formalin‐fixed sections was performed by deparaffinization and rehydration, followed by antigen retrieval by heating in a pressure cooker (121°C) for 5 minutes in 10 mM sodium citrate, pH 6.0, as described. ( 19 ) Peroxidase activity was blocked by incubation in 3% hydrogen peroxide for 10 minutes. Sections were rinsed 3 times in phosphate‐buffered saline (PBS)/PBS‐Tween 20 (PBST; 0.1% Tween‐20) and incubated in Dako Protein Block (Dako, Carpinteria, CA) at room temperature for 1 hour.…”

Section: Methodsmentioning

confidence: 99%

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Hepatocellular Protein Arginine Methyltransferase 1 Suppresses Alcohol‐Induced Hepatocellular Carcinoma Formation by Inhibition of Inducible Nitric Oxide Synthase

et al. 2020

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Alcohol is a well-established risk factor for hepatocellular carcinoma (HCC), but the mechanisms by which alcohol promotes liver cancer are not well understood. Studies suggest that ethanol may enhance tumor progression by increasing hepatocyte proliferation and through alcohol-induced liver inflammation. Protein arginine methyltransferase 1 (PRMT1) is the main enzyme responsible for cellular arginine methylation. Asymmetric dimethyl arginine, produced by PRMT1, is a potent inhibitor of nitric oxide synthases. PRMT1 is implicated in the development of several types of tumors and cardiovascular disease. Our previous work has shown that PRMT1 in the liver regulates hepatocyte proliferation and oxidative stress and protects from alcohol-induced liver injury. However, its role in HCC development remains controversial. In this study, we found that hepatocyte-specific PRMT1-knockout mice develop an increased number of tumors in an N-nitrosodiethylamine (DEN) alcohol model of liver tumorigenesis in mice. This effect was specific to the alcohol-related component because wild-type and knockout mice developed similar tumor numbers in the DEN model without the addition of alcohol. We found that in the presence of alcohol, the increase in tumor number was associated with increased proliferation in liver and tumor, increased WNT/β-catenin signaling, and increased inflammation. We hypothesized that increased inflammation was due to increased oxidative and nitrosative stress in knockout mice. By blocking excess nitric oxide production using an inducible nitric oxide synthase inhibitor, we reduced hepatocyte death and inflammation in the liver and prevented the increase in WNT/β-catenin signaling, proliferation, and tumor number in livers of knockout mice. Conclusion: PRMT1 is an important protection factor from alcohol-induced liver injury, inflammation, and HCC development. (Hepatology Communications 2020;4:790-808). SEE EDITORIAL ON PAGE 787H epatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide. (1,2) Unlike other cancers with known risk factors, molecular mechanisms of HCC development are not completely understood. Most patients with HCC have a history of chronic liver disease and cirrhosis, (3) but cirrhosis associated with hepatitis B and C and chronic alcohol drinking account for most cases. (4) About 40% of individuals who chronically consume alcohol develop fatty liver, which can advance to alcoholic hepatitis and/or cirrhosis. Although there have been conflicting findings, currently it is accepted that

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“…Recent studies demonstrate that oxidative stress could be regulated by the protein arginine methylation system. ( 5,6 )…”

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confidence: 99%

The Protective Function of PRMT1 in Alcohol‐Induced Hepatocellular Carcinoma

Jeong

2020

Hepatol Commun

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Protein arginine methyl transferase 1– and Jumonji C domain‐containing protein 6–dependent arginine methylation regulate hepatocyte nuclear factor 4 alpha expression and hepatocyte proliferation in mice

Abstract: Taken together, these data suggest that PRMT1 inhibition, such as induced by alcohol, may result in epigenetic changes leading to loss of Hnf4α. This effect may contribute to alcohol's ability to promote liver tumors. (Hepatology 2018;67:1109-1126).

Cited by 51 publications

References 41 publications

Deficiency of Mitochondrial Glycerol 3‐Phosphate Dehydrogenase Contributes to Hepatic Steatosis

Deficiency of Mitochondrial Glycerol 3‐Phosphate Dehydrogenase Contributes to Hepatic Steatosis

Hepatocellular Protein Arginine Methyltransferase 1 Suppresses Alcohol‐Induced Hepatocellular Carcinoma Formation by Inhibition of Inducible Nitric Oxide Synthase

The Protective Function of PRMT1 in Alcohol‐Induced Hepatocellular Carcinoma

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