Myeloid beta-arrestin 2 depletion attenuates metabolic dysfunction-associated steatohepatitis via the metabolic reprogramming of macrophages.
Journal
Cell metabolism
Journal Volume
36
Journal Issue
10
Start Page
2281
End Page
2297
ISSN
1932-7420
Date Issued
2024-10-01
Author(s)
Wei, Xiaoli
Wu, Dongqing
Li, Jing
Wu, Miaomiao
Li, Qianhui
Che, Zhaodi
Cheng, Xu
Cheng, Qianying
Yin, Fan
Zhang, Hao
Wang, Xuefu
Abtahi, Shabnam
Zuo, Li
Hang, Lei
Ma, Lili
Liu, Xiaoying
Turner, Jerrold R
Wang, Hua
Xiao, Jia
Wang, Fei
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.
Subjects
IRG1
MASLD
itaconate
macrophage polarization
metabolic reprogramming
β-arrestin 2
Type
journal article