Myeloid beta-arrestin 2 depletion attenuates metabolic dysfunction-associated steatohepatitis via the metabolic reprogramming of macrophages

Macrophage-mediated inflammation has been implicated in the pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH); however, the immunometabolic program underlying the regulation of macrophage activation remains unclear. Beta-arrestin 2, a multifunctional adaptor protein, is highly expressed in bone marrow tissues and macrophages and is involved in metabolism disorders. Here, we observed that β-arrestin 2 expression was significantly increased in the liver macrophages and circulating monocytes of patients with MASH compared with healthy controls and positively correlated with the severity of metabolic dysfunction-associated steatotic liver disease (MASLD). Global or myeloid Arrb2 deficiency prevented the development of MASH in mice. Further study showed that β-arrestin 2 acted as an adaptor protein and promoted ubiquitination of immune responsive gene 1 (IRG1) to prevent increased itaconate production in macrophages, which resulted in enhanced succinate dehydrogenase activity, thereby promoting the release of mitochondrial reactive oxygen species and M1 polarization. Myeloid β-arrestin 2 depletion may be a potential approach for MASH.

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Publication Details

Journal
Cell Metabolism
Published
2024-09-20
DOI
https://doi.org/10.1016/j.cmet.2024.08.010
Citations
28
Primary Topic
Liver Disease Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
10.83

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article

Myeloid beta-arrestin 2 depletion attenuates metabolic dysfunction-associated steatohepatitis via the metabolic reprogramming of macrophages

Wei‐Ting Kuo, Shabnam Abtahi, Xuefu Wang, Lei Hang et al.
28 citations
Cell Metabolism
Liver Disease Diagnosis and Treatment
10.83
article

Myeloid beta-arrestin 2 depletion attenuates metabolic dysfunction-associated steatohepatitis via the metabolic reprogramming of macrophages

Wei‐Ting Kuo, Shabnam Abtahi, Xuefu Wang, Lei Hang, Zhaodi Che, Jerrold R. Turner, Dongqing Wu, Xiaoying Liu, Cheng Xu, Fan Yin, Li Zuo, Xiaoli Wei, Qianhui Li, Miaomiao Wu, Jia Xiao, Jing Li, Lili Ma, Qianying Cheng, Hao Zhang, Hua Wang, Fei Wang
article en
28 citations

Abstract

Macrophage-mediated inflammation has been implicated in the pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH); however, the immunometabolic program underlying the regulation of macrophage activation remains unclear. Beta-arrestin 2, a multifunctional adaptor protein, is highly expressed in bone marrow tissues and macrophages and is involved in metabolism disorders. Here, we observed that β-arrestin 2 expression was significantly increased in the liver macrophages and circulating monocytes of patients with MASH compared with healthy controls and positively correlated with the severity of metabolic dysfunction-associated steatotic liver disease (MASLD). Global or myeloid Arrb2 deficiency prevented the development of MASH in mice. Further study showed that β-arrestin 2 acted as an adaptor protein and promoted ubiquitination of immune responsive gene 1 (IRG1) to prevent increased itaconate production in macrophages, which resulted in enhanced succinate dehydrogenase activity, thereby promoting the release of mitochondrial reactive oxygen species and M1 polarization. Myeloid β-arrestin 2 depletion may be a potential approach for MASH.

Cell MetabolismVol. 36(10)
Brigham and Women's Hospital (US), Sun Yat-sen University (CN), Anhui University of Science and Technology (CN), Anhui Medical University (CN), The Seventh Affiliated Hospital of Sun Yat-sen University (CN), First Affiliated Hospital of Gannan Medical University (CN), First Affiliated Hospital of Anhui Medical University (CN), First Affiliated Hospital of Jinan University (CN)
National Natural Science Foundation of China, University of Science and Technology of China, National Key Research and Development Program of China
Zero hunger
Openalex Percentile: Top 1%
Liver Disease Diagnosis and Treatment
10.83
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