The protective roles of augmenter of liver regeneration in hepatocytes in the non-alcoholic fatty liver disease

Dong, Yuan; Zhang, Yuejie; Feng, Yingmei; An, Wei

doi:10.3389/fphar.2022.928606

Cited by 1 publication

(1 citation statement)

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“…Furthermore, deletion of ALR expression in mice leads to steatohepatitis and hepatocellular carcinoma [23,24]. Several reports have underlined the important role of ALR as an anti-apoptotic, anti-oxidative, and cell survival factor after injury (reviewed in [25][26][27]). Interestingly, although reduced hepatic ALR expression levels were found in liver diseases, such as cholestasis [28] and NASH [21], the underlying molecular mechanism for its regulation under these conditions is less clear.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-1ß Attenuates Expression of Augmenter of Liver Regeneration (ALR) by Regulating HNF4α Independent of c-Jun

Nimphy

Ibrahim

Dayoub

et al. 2023

IJMS

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Inflammasomes and innate immune cells have been shown to contribute to liver injury, thereby activating Kupffer cells, which release several cytokines, including IL-6, IL-1ß, and TNFα. Augmenter of liver regeneration (ALR) is a hepatotropic co-mitogen that was found to have anti-oxidative and anti-apoptotic properties and to attenuate experimental non-alcoholic fatty liver disease (NAFLD) and cholestasis. Additionally, hepatic ALR expression is diminished in patients with NAFLD or cholestasis, but less is known about the mechanisms of its regulation under these conditions. Therefore, we aimed to investigate the role of IL-1ß in ALR expression and to elucidate the molecular mechanism of this regulation in vitro. We found that ALR promoter activity and mRNA and protein expression were reduced upon treatment with IL-1ß. Early growth response protein-1 (Egr-1), an ALR inducer, was induced by IL-1ß but could not activate ALR expression, which may be attributed to reduced Egr-1 binding to the ALR promoter. The expression and nuclear localization of hepatocyte nuclear factor 4 α (HNF4α), another ALR-inducing transcription factor, was reduced by IL-1ß. Interestingly, c-Jun, a potential regulator of ALR and HNF4α, showed increased nuclear phosphorylation levels upon IL-1ß treatment but did not change the expression of ALR or HNF4α. In conclusion, this study offers evidence regarding the regulation of anti-apoptotic and anti-oxidative ALR by IL-1ß through reduced Egr-1 promoter binding and diminished HNF4α expression independent of c-Jun activation. Low ALR tissue levels in NAFLD and cholestatic liver injury may be caused by IL-1ß and contribute to disease progression.

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