Augmenter of Liver Regeneration Crotonylation Assists in Mitochondria-ER Contact to Alleviate Hepatic Steatosis

IF 7.1 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

Cellular and Molecular Gastroenterology and Hepatology Pub Date : 2025-01-01 DOI:10.1016/j.jcmgh.2024.101436

Xiao-lin Wang , Jia-hao He , Ping Xie, Yuan Wu, Ling-yue Dong, Wei An

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引用次数: 0

Abstract

Background & Aims

Crotonylation (Kcr), a newly identified post-translation modification (PTM), has been confirmed to be involved in diverse biological processes and human diseases as well. Metabolic dysfunction-associated steatotic liver disease (MASLD) poses a serious threat to people’s health. Augmenter of liver regeneration (ALR) is an important liver regulatory protein, and the insufficiency of ALR expression is reported to accelerate liver steatosis progression to liver fibrosis or even hepatic carcinoma (HCC). However, the connection between dysregulated ALR crotonylation and MASLD pathogenesis remains largely unknown.

Methods

Steatotic liver samples from human and Western diet (WD)-fed mice were employed for detecting Kcr levels. Mitochondrial function and mitochondria-ER interaction (MAM) relevant to ALR-Kcr modification was evaluated for hepatocyte lipid metabolism both in in vivo and in vitro experiments.

Results

Global protein crotonylation (Kcr) as well as ALR-Kcr was significantly decreased in liver samples of patients with MASLD and WD mice. Histone deacetylase1/2 (HDAC1/2) and lysine acetyltransferase 8 (KAT8) were identified responsible for regulation of ALR-Kcr, which takes place at lysine 78 (K78). The decrease of ALR crotonylation might be related to the imbalance between HDAC1/2 and KAT8 expression, inhibited its interaction with MFN2, expanding MAM distance and impairing mitochondrial lipid metabolism, and consequently deteriorating hepatic steatosis.

Conclusions

The insufficient ALR crotonylation might be a crucial mechanism contributing to the pathogenesis of MASLD. Keeping ALR crotonylation level would be beneficial for the prevention and treatment of MASLD.

Abstract Image

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肝脏再生促进剂（ALR）的巴豆酰化有助于线粒体-ER 接触，从而缓解肝脏脂肪变性。

背景与目的：Crotonylation （Kcr）是一种新发现的翻译后修饰（PTM），已被证实参与多种生物过程和人类疾病。代谢功能障碍相关性脂肪变性肝病（MASLD）严重威胁着人们的健康。肝再生增强蛋白（Augmenter of liver regeneration， ALR）是一种重要的肝脏调节蛋白，有报道称ALR表达不足会加速肝脏脂肪变性向肝纤维化甚至肝癌的发展。然而，失调的ALR巴豆酰化与MASLD发病机制之间的联系在很大程度上仍然未知。方法：采用人脂肪变性肝和西式饮食小鼠脂肪变性肝检测Kcr水平。在体内和体外实验中评估了与ALR-Kcr修饰相关的线粒体功能和线粒体-内质网相互作用（MAM）对肝细胞脂质代谢的影响。结果：MASLD患者和WD小鼠肝脏样品中总蛋白巴豆酰化（Global protein crotonylation, Kcr）和ALR-Kcr显著降低。组蛋白去乙酰化酶1/2 （HDAC1/2）和赖氨酸乙酰转移酶8 （KAT8）被鉴定为在赖氨酸78 （K78）位点调控ALR-Kcr。ALR crotonylation的降低可能与HADC1/2和KAT8表达失衡有关，抑制了其与MFN2的相互作用，扩大了MAM距离，损害了线粒体脂质代谢，从而恶化了肝脏脂肪变性。结论：ALR巴豆酰化不足可能是MASLD发病的重要机制。保持ALR的crotonylation水平有利于MASLD的预防和治疗。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cellular and Molecular Gastroenterology and Hepatology Medicine-Gastroenterology

CiteScore

13.00

自引率

2.80%

发文量

246

审稿时长

42 days

期刊介绍： "Cell and Molecular Gastroenterology and Hepatology (CMGH)" is a journal dedicated to advancing the understanding of digestive biology through impactful research that spans the spectrum of normal gastrointestinal, hepatic, and pancreatic functions, as well as their pathologies. The journal's mission is to publish high-quality, hypothesis-driven studies that offer mechanistic novelty and are methodologically robust, covering a wide range of themes in gastroenterology, hepatology, and pancreatology. CMGH reports on the latest scientific advances in cell biology, immunology, physiology, microbiology, genetics, and neurobiology related to gastrointestinal, hepatobiliary, and pancreatic health and disease. The research published in CMGH is designed to address significant questions in the field, utilizing a variety of experimental approaches, including in vitro models, patient-derived tissues or cells, and animal models. This multifaceted approach enables the journal to contribute to both fundamental discoveries and their translation into clinical applications, ultimately aiming to improve patient care and treatment outcomes in digestive health.