A novel role of astrocyte elevated gene‐1 (AEG‐1) in regulating nonalcoholic steatohepatitis (NASH)

Srivastava, Jyoti; Robertson, Chadia L.; Ebeid, Kareem; Dozmorov, Mikhail G.; Rajasekaran, Devaraja; Mendoza, Rachel G.; Siddiq, Ayesha; Akiel, Maaged; Jariwala, Nidhi; Shen, Xue; Windle, Jolene J.; Subler, Mark A.; Mukhopadhyay, Nitai D.; Giashuddin, Shah; Ghosh, Shobha; Lai, Zhao; Chen, Yidong; Fisher, Paul B.; Salem, Aliasger K.; Sanyal, Arun J.; Sarkar, Devanand

doi:10.1002/hep.29230

Cited by 26 publications

(56 citation statements)

References 41 publications

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“…Our extensive studies over the last decade have firmly established that Astrocyte elevated gene-1 (AEG-1)/metadehrin (MTDH) functions as a major oncogene for HCC and is highly overexpressed in HCC patients of diverse etiologies by multiple mechanisms including genomic amplification (12–22). AEG-1 knockout mice (AEG-1−/−) exhibit complete resistance to N-nitrosodiethylamine (DEN) and phenobarbital (PB)-induced HCC (20).…”

Section: Introductionmentioning

confidence: 99%

Astrocyte Elevated Gene-1 Regulates Macrophage Activation in Hepatocellular Carcinogenesis

et al. 2018

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Chronic inflammation is a known hallmark of cancer and is central to the onset and progression of hepatocellular carcinoma (HCC). Hepatic macrophages play a critical role in the inflammatory process leading to HCC. The oncogene Astrocyte elevated gene-1 () regulates NFκB activation, and germline knockout of in mice (AEG-1) results in resistance to inflammation and experimental HCC. In this study, we developed conditional hepatocyte- and myeloid cell-specific AEG-1 mice (AEG-1 and AEG-1, respectively) and induced HCC by treatment with N-nitrosodiethylamine (DEN) and phenobarbital (PB). AEG-1 mice exhibited a significant reduction in disease severity compared with control littermates, while AEG-1 mice were profoundly resistant. , AEG-1 hepatocytes exhibited increased sensitivity to stress and senescence. Notably, AEG-1 macrophages were resistant to either M1 or M2 differentiation with significant inhibition in migration, endothelial adhesion, and efferocytosis activity, indicating that AEG-1 ablation renders macrophages functionally anergic. These results unravel a central role of AEG-1 in regulating macrophage activation and indicate that AEG-1 is required in both tumor cells and tumor microenvironment to stimulate hepatocarcinogenesis. These findings distinguish a novel role of macrophage-derived oncogene AEG-1 from hepatocellular AEG-1 in promoting inflammation and driving tumorigenesis. .

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Section: Introductionmentioning

confidence: 99%

Astrocyte Elevated Gene-1 Regulates Macrophage Activation in Hepatocellular Carcinogenesis

et al. 2018

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“…The development of NAFLD is strongly related to hepatic steatosis, due to the rate of fatty acid input ( de novo fatty acid synthesis) exceeds the rate of fatty acid output (fatty acid oxidation) (Goedeke et al, 2018). Therefore, the simultaneous effective suppression of de novo fatty acid synthesis and stimulation of fatty acid oxidation offers an attractive therapeutic strategy for NAFLD (Srivastava et al, 2017). The current study presents the first attempt to demonstrate the following.…”

Section: Discussionmentioning

confidence: 99%

“…Accumulating research has demonstrated that imbalanced fatty acid metabolism plays a crucial initial role in the onset and perpetuation of hepatic steatosis (Fabbrini, Sullivan, & Klein, 2010). Imbalanced fatty acid metabolism is characterized by increased de novo fatty acid synthesis and decreased fatty acid oxidation, which subsequently lead to excessive lipid accumulation and steatosis (Goedeke et al, 2018; Srivastava et al, 2017). Thus the identification of a potential target to attenuate fatty acid metabolism disorder may provide the basis for novel therapeutic strategies to alleviate NAFLD.…”

Section: Introductionmentioning

confidence: 99%

Sirtuin 3‐mediated deacetylation of acyl‐CoA synthetase family member 3 by protocatechuic acid attenuates non‐alcoholic fatty liver disease

Sun

Kang

Zhao

et al. 2020

British J Pharmacology

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Background and Purpose: Hepatic fatty acid metabolism disorder, a key pathogenic mechanism underlying non-alcoholic fatty liver disease (NAFLD), is associated with the hyperacetylation of mitochondrial enzymes. Acyl-CoA synthetase family member 3 (ACSF3), which is involved in the regulation of fatty acid metabolism, was predicted to contain lysine acetylation sites related to the mitochondrial deacetylase sirtuin 3 (SIRT3). The purpose of this study was to explore the underlying mechanism by which SIRT3 deacetylates ACSF3 in NAFLD and the protective effect of the natural phenolic compound protocatechuic acid (PCA) against fatty acid metabolism disorder via the SIRT3/ACSF3 pathway. Experimental Approach: The role of protocatechuic acid and its molecular mechanism in NAFLD were detected in rats and SIRT3-knockout mice fed a high-fat diet (HFD) and in AML-12 cells treated with palmitic acid (PA). Key Results: Pharmacological treatment with protocatechuic acid significantly attenuated high-fat diet-induced fatty acid metabolism disorder in NAFLD. Molecular docking assays showed that protocatechuic acid specifically bound SIRT3 as a substrate and increased SIRT3 protein expression. However, the protective role of protocatechuic acid was abolished by SIRT3 knockdown, which increased ACSF3 expression and exacerbated fatty acid metabolism disorder. Mechanistically, SIRT3 was shown to specifically regulate the acetylation and degradation of ACSF3, which govern the capacity of ACSF3 to mediate fatty acid metabolism disorder during NAFLD. Conclusion and Implications: SIRT3-mediated ACSF3 deacetylation is a novel molecular mechanism in NAFLD therapy and protocatechuic acid confers protection against high-fat diet-and palmitic acid-induced hepatic fatty acid metabolism disorder through the SIRT3/ACSF3 pathway.

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“…NASH livers are more injured than livers with isolated steatosis, which more likely leads to progressive fibrosis and eventual liver-associated illness and death (3). The molecular players that modulate disease pathogenesis are starting to be identified, enabling translation of research findings to clinical trials (4,5). However, no optimum therapy is yet available, suggesting that a more comprehensive understanding of the onset and progression of NAFLD is needed.…”

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confidence: 99%

“…The shift from isolated steatosis to NASH is defined histologically as emergence of liver inflammation and hepatocellular injury. The most common theory explaining this shift is the "double-hit hypothesis" (3,5,6). The first hit consists mainly of lipid accumulation, whereas the second comprises sequential innate immune responses (6)(7)(8).…”

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confidence: 99%

HSPA12A Is a Novel Player in Nonalcoholic Steatohepatitis via Promoting Nuclear PKM2-Mediated M1 Macrophage Polarization

Kong

Cheng

et al. 2018

Diabetes

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Nonalcoholic steatohepatitis (NASH) is the most prevalent cause of chronic liver disease worldwide. Macrophagemediated inflammation plays a critical role in NASH pathogenesis; however, optimum therapies for macrophage activation and NASH remain elusive. HSPA12A encodes a novel member of the HSP70 family. Here, we report that NASH patients showed increased hepatic HSPA12A expression and serum HSPA12A contents. Intriguingly, knockout of HSPA12A (Hspa12a 2/2) in mice attenuated high-fat diet (HFD)-induced hepatic steatosis and injury. HFD-induced macrophage polarization toward an M1 phenotype and inflammatory responses in the liver of Hspa12a 2/2 mice were also attenuated. Loss-and gain-of-function studies revealed that the de novo lipogenesis in hepatocytes was regulated by the paracrine effects of macrophage HSPA12A rather than by hepatocyte HSPA12A. In-depth molecular analysis revealed that HSPA12A interacted with the M2 isoform of pyruvate kinase (PKM2) in macrophages and increased its nuclear translocation, thereby promoting M1 polarization and secretion of proinflammatory M1 cytokines; this led, ultimately, to hepatocyte steatosis via paracrine effects. Taken together, these findings show that HSPA12A acts as a novel regulator of M1 macrophage polarization and NASH pathogenesis by increasing nuclear PKM2. Strategies that inhibit macrophage HSPA12A might be a potential therapeutic intervention for NASH.

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A novel role of astrocyte elevated gene‐1 (AEG‐1) in regulating nonalcoholic steatohepatitis (NASH)

Cited by 26 publications

References 41 publications

Astrocyte Elevated Gene-1 Regulates Macrophage Activation in Hepatocellular Carcinogenesis

Astrocyte Elevated Gene-1 Regulates Macrophage Activation in Hepatocellular Carcinogenesis

Sirtuin 3‐mediated deacetylation of acyl‐CoA synthetase family member 3 by protocatechuic acid attenuates non‐alcoholic fatty liver disease

HSPA12A Is a Novel Player in Nonalcoholic Steatohepatitis via Promoting Nuclear PKM2-Mediated M1 Macrophage Polarization

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