ARRB1 inhibits non-alcoholic steatohepatitis progression by promoting GDF15 maturation

Zhang, Zechuan; Xu, Xiaoliang; Tian, Wen‐de; Jiang, Runqiu; Lu, Yijun; Sun, Qing‐Fu; Fu, Rao; He, Qifeng; Wang, Jincheng; Yang, Lei; Yu, Hailong; Sun, Beicheng

doi:10.1016/j.jhep.2019.12.004

Cited by 41 publications

(42 citation statements)

References 48 publications

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“…40 In this studies, we found VVYP ameliorated MCD diet-induced liver injuries via reducing ALT/AST/ TG/NEFA levels, promoting lipid deposition, regulating expressions Mice fed by MCD diet and HFD have been broadly applied in NASH-related research. 41,42 Multiple mechanisms have been proposed in the MCD model, which closely replicated human NASH histological phenotype within a relatively short period. 43 Methionine deficiency initially resulted in oxidative stress and alterations in adipokines and cytokines, which were considered to drive the development of inflammation in animals, whereas choline deficiency contributed more to the phenotype of hepatic steatosis.…”

Section: Discussionmentioning

confidence: 96%

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Val‐Val‐Tyr‐Pro protects against non‐alcoholic steatohepatitis in mice by modulating the gut microbiota and gut‐liver axis activation

Xie

Zhang

Yuan

et al. 2021

J Cellular Molecular Medi

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Val‐Val‐Tyr‐Pro (VVYP) peptide is one of the main active components of Globin digest (GD). Our previous studies indicated that VVYP could protect against acetaminophen and carbon tetrachloride‐induced acute liver failure in mice and decrease blood lipid level. However, the effects and underlying mechanisms of VVYP in the treatment of non‐alcoholic steatohepatitis (NASH) have not been discovered. Our present study was designed to investigate the preventive effect of VVYP on NASH and its underlying specific mechanisms. We found that VVYP inhibited the cytotoxicity and lipid accumulation in L‐02 cells that were exposed to a mixture of free fatty acid (FFA). VVYP effectively alleviated the liver injury induced by methionine‐choline‐deficient (MCD) diet, demonstrated by reducing the levels of serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST)/triglycerides (TG)/non‐esterified fatty acids (NEFA) and improving liver histology. VVYP decreased expression levels of lipid synthesis‐related genes and reduced levels of the proinflammation cytokines in the liver of mice fed by MCD diet. Moreover, VVYP inhibited the increased level of LPS and reversed the liver mitochondria dysfunction induced by MCD diet. Meanwhile, VVYP significantly increased the abundance of beneficial bacteria such as Eubacteriaceae , coriobacteriacease, Desulfovibrionaceae, S24‐7 and Bacteroidia in high‐fat diet (HFD)‐fed mice, however, VVYP reduced the abundance of Lactobacillus . Moreover, VVYP conferred the protective effect of intestinal barrier via promoting the expression of the mucins and tight junction (TJ)‐associated genes and inhibited subsequent liver inflammatory responses. These results indicated that the protective role of VVYP on NASH is mediated by modulating gut microbiota imbalance and related gut‐liver axis activation. VVYP might be a promising drug candidate for NASH.

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Section: Discussionmentioning

confidence: 96%

“…Mice fed by MCD diet and HFD have been broadly applied in NASH‐related research 41,42 . Multiple mechanisms have been proposed in the MCD model, which closely replicated human NASH histological phenotype within a relatively short period 43 .…”

Section: Discussionmentioning

confidence: 99%

Val‐Val‐Tyr‐Pro protects against non‐alcoholic steatohepatitis in mice by modulating the gut microbiota and gut‐liver axis activation

Xie

Zhang

Yuan

et al. 2021

J Cellular Molecular Medi

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“…In this issue of Journal of Hepatology, Zhang et al present a first thorough study of the role of ARRB1 in NASH, and for the first time provide a mechanistic link between ARRB1 and GDF15. 19 They found a downregulation of ARRB1 mRNA and protein in livers of 40 patients with NASH compared to 40 normal controls, and a negative correlation with the NAFLD activity score, serum aspartate and alanine aminotransferase, and triglycerides. Unfortunately, the fibrosis stage was not documented.…”

mentioning

confidence: 95%

“…In line with enhanced hepatocyte inflammation, the high-fat diet in Arrb1 knockout mice induced upregulation of hepatic PPARc that attenuates steatosis and inflammation, and downregulation of PPARa that enhances b-oxidation and exhibits anti-steatotic and anti-inflammatory effects in NASH. 19,20 Thus, the net effect of ARRB1 modulating the expression of PPAR subspecies is complex and needs further study.…”

mentioning

confidence: 99%

“…Here, AAV-pro-GDF15 improved steatosis only in wild-type mice, confirming the connection of ARRB1 and GDF15. 19 In light of prior data in the CCl 4 mouse model linking reduced GDF15 expression to increased liver inflammation and elevated serum TNF-a and IL-6, 21 3 mechanisms of GDF15 action in NASH can be proposed. First, hepatocyte GDF15 binds to one of the GDF15 receptors on hepatocytes in an auto-or paracrine manner, preventing excess lipid accumulation and subsequent metabolic disturbance and inflammation; second, GDF15 may bind to GFRAL in the brain, to signal reduced appetite and result in weight loss; 16 third, GDF15 exerts a profibrogenic effect by yet ill-defined mechanisms.…”

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confidence: 99%

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β-arrestin: Dr Jekyll and Mr Hyde in NASH and fibrosis

Abé

Schuppan

2020

Journal of Hepatology

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T‐2 Toxin‐Mediated β‐Arrestin‐1 O‐GlcNAcylation Exacerbates Glomerular Podocyte Injury via Regulating Histone Acetylation

Li,

Sun,

Zhu

et al. 2023

Advanced Science

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T‐2 toxin causes renal dysfunction with proteinuria and glomerular podocyte damage. This work explores the role of metabolic disorder/reprogramming‐mediated epigenetic modification in the progression of T‐2 toxin‐stimulated podocyte injury. A metabolomics experiment is performed to assess metabolic responses to T‐2 toxin infection in human podocytes. Roles of protein O‐linked‐N‐acetylglucosaminylation (O‐GlcNAcylation) in regulating T‐2 toxin‐stimulated podocyte injury in mouse and podocyte models are assessed. O‐GlcNAc target proteins are recognized by mass spectrometry and co‐immunoprecipitation experiments. Moreover, histone acetylation and autophagy levels are measured. T‐2 toxin infection upregulates glucose transporter type 1 (GLUT1) expression and enhances hexosamine biosynthetic pathway in glomerular podocytes, resulting in a significant increase in β‐arrestin‐1 O‐GlcNAcylation. Decreasing β‐arrestin‐1 or O‐GlcNAc transferase (OGT) effectively prevents T‐2 toxin‐induced renal dysfunction and podocyte injury. Mechanistically, O‐GlcNAcylation of β‐arrestin‐1 stabilizes β‐arrestin‐1 to activate the mammalian target of rapamycin (mTOR) pathway as well as to inhibit autophagy during podocyte injury by promoting H4K16 acetylation. To sum up, OGT‐mediated β‐arrestin‐1 O‐GlcNAcylation is a vital regulator in the development of T‐2 toxin‐stimulated podocyte injury via activating the mTOR pathway to suppress autophagy. Targeting β‐arrestin‐1 or OGT can be a potential therapy for T‐2 toxin infection‐associated glomerular injury, especially podocyte injury.

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ARRB1 inhibits non-alcoholic steatohepatitis progression by promoting GDF15 maturation

Cited by 41 publications

References 48 publications

Val‐Val‐Tyr‐Pro protects against non‐alcoholic steatohepatitis in mice by modulating the gut microbiota and gut‐liver axis activation

Val‐Val‐Tyr‐Pro protects against non‐alcoholic steatohepatitis in mice by modulating the gut microbiota and gut‐liver axis activation

β-arrestin: Dr Jekyll and Mr Hyde in NASH and fibrosis

T‐2 Toxin‐Mediated β‐Arrestin‐1 O‐GlcNAcylation Exacerbates Glomerular Podocyte Injury via Regulating Histone Acetylation

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