Amelioration of hepatic steatosis by dietary essential amino acid-induced ubiquitination

Zhang, Yansong; Lin, Siyuan; Peng, Jingyu; Liang, Xinming; Yang, Qi; Bai, Xue; Li, Yajuan; Li, Jinhua; Dong, Wei; Wang, Yue; Huang, Ying; Pei, Yumeng; Guo, Jiabao; Zhao, Wanni; Zhang, Zhe; Liu, Min; Zhu, Alan Jian

doi:10.1016/j.molcel.2022.01.021

Cited by 34 publications

(32 citation statements)

References 61 publications

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“…This circuit establishes feed-forward regulation of peptide uptake, where imported peptides stimulate expression of their own transporter through ubiquitin-dependent degradation of Cup9. Notably, amino acids also activate Ubr1 orthologs from higher eukaryotes to regulate lipid droplets, suggestive of intricate metabolic regulation similar to that in yeast ( Zhang et al., 2022 ).…”

Section: Numerous N- and C-degron Pathwaysmentioning

confidence: 93%

How the ends signal the end: Regulation by E3 ubiquitin ligases recognizing protein termini

2022

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Section: Numerous N- and C-degron Pathwaysmentioning

confidence: 93%

How the ends signal the end: Regulation by E3 ubiquitin ligases recognizing protein termini

2022

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“…Leucine and isoleucine, two BCAAs, were strongly associated with the activation of E3 ubiquitin ligase Ubr1, targeting Plin2 for degradation. It was demonstrated that the amino acid-induced Ubr1 activity was necessary to prevent steatosis in mouse livers and cultured human hepatocytes [ 41 ]. Furthermore, a previous cross-sectional study of 102 subjects indicated that elevated plasma glutamate levels were associated with increased CIMT, independently of established CVD risk factors [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Metabolomics to identify fingerprints of carotid atherosclerosis in nonobese metabolic dysfunction-associated fatty liver disease

Shao

Lei³

et al. 2023

J Transl Med

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Background/aims Nonobese metabolic dysfunction-associated fatty liver disease (MAFLD) is paradoxically associated with improved metabolic and pathological features at diagnosis but similar cardiovascular diseases (CVD) prognosis to obese MAFLD. We aimed to utilize the metabolomics to identify the potential metabolite profiles accounting for this phenomenon. Methods This prospective multicenter cross-sectional study was conducted in China enrolling derivation and validation cohorts. Liquid chromatography coupled with mass spectrometry and gas chromatography-mass spectrometry were applied to perform a metabolomics measurement. Results The study involved 120 MAFLD patients and 60 non-MAFLD controls in the derivation cohort. Controls were divided into two groups according to the presence of carotid atherosclerosis (CAS). The MAFLD group was further divided into nonobese MAFLD with/without CAS groups and obese MAFLD with/without CAS groups. Fifty-six metabolites were statistically significant for discriminating the six groups. Among the top 10 metabolites related to CAS in nonobese MAFLD, only phosphatidylethanolamine (PE 20:2/16:0), phosphatidylglycerol (PG 18:0/20:4) and de novo lipogenesis (16:0/18:2n-6) achieved significant areas under the ROC curve (AUCs, 0.67, p = 0.03; 0.79, p = 0.02; 0.63, p = 0.03, respectively). The combination of these three metabolites and liver stiffness achieved a significantly higher AUC (0.92, p < 0.01). In obese MAFLD patients, cystine was found to be significant with an AUC of 0.69 (p = 0.015), followed by sphingomyelin (SM 16:1/18:1) (0.71, p = 0.004) and de novo lipogenesis (16:0/18:2n-6) (0.73, p = 0.004). The combination of these three metabolites, liver fat content and age attained a significantly higher AUC of 0.91 (p < 0.001). The AUCs of these metabolites remained highly significant in the independent validation cohorts involving 200 MAFLD patients and 90 controls. Conclusions Diagnostic models combining different metabolites according to BMI categories could raise the accuracy of identifying subclinical CAS. Trial registration The study protocol was approved by the local ethics committee and all the participants have provided written informed consent (Approval number: [2014] No. 112, registered at the Chinese Clinical Trial Registry, ChiCTR-ChiCTR2000034197) Graphical Abstract

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“…It is reported that dysregulation of amino acids and choline contributed to lipid accumulation and chronic inflammation in NAFLD ( Chen and Vitetta, 2020 ). A study revealed that dietary essential amino acids ameliorated hepatic steatosis by inducing polyubiquitination of Plin2 in NAFLD mice ( Zhang et al., 2022 ). Another study reported that plasma concentration of several amino acids (including branched-chain and aromatic amino acids) was altered in NAFLD, and the alteration of specific amino acids (such as alanine, glutamate and glycine) might be used for early detection of NAFLD ( Trico et al., 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Lingguizhugan decoction improves non-alcoholic steatohepatitis partially by modulating gut microbiota and correlated metabolites

Zhu

Wang

et al. 2023

Front. Cell. Infect. Microbiol.

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BackgroundLingguizhugan decoction is a traditional Chinese medicine prescription that has been used to improve non-alcoholic fatty liver disease and its progressive form, non-alcoholic steatohepatitis (NASH). However, the anti-NASH effects and underlying mechanisms of Lingguizhugan decoction remain unclear.MethodsMale Sprague-Dawley rats were fed a methionine- and choline-deficient (MCD) diet to induce NASH, and then given Lingguizhugan decoction orally for four weeks. NASH indexes were evaluated by histopathological analysis and biochemical parameters including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), liver triglycerides (TG), etc. Fecal samples of rats were subjected to profile the changes of gut microbiota and metabolites using 16S rRNA sequencing and ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS). Bioinformatics was used to identify Lingguizhugan decoction reversed candidates, and Spearman’s correlation analysis was performed to uncover the relationship among gut microbiota, fecal metabolites, and NASH indexes.ResultsFour-week Lingguizhugan decoction treatment ameliorated MCD diet-induced NASH features, as evidenced by improved hepatic steatosis and inflammation, as well as decreased serum AST and ALT levels. Besides, Lingguizhugan decoction partially restored the changes in gut microbial community composition in NASH rats. Meanwhile, the relative abundance of 26 genera was significantly changed in NASH rats, and 11 genera (such as odoribacter, Ruminococcus_1, Ruminococcaceae_UCG-004, etc.) were identified as significantly reversed by Lingguizhugan decoction. Additionally, a total of 99 metabolites were significantly altered in NASH rats, and 57 metabolites (such as TDCA, Glutamic acid, Isocaproic acid, etc.) enriched in different pathways were reversed by Lingguizhugan decoction. Furthermore, Spearman’s correlation analyses revealed that most of the 57 metabolites were significantly correlated with 11 genera and NASH indexes.ConclusionLingguizhugan decoction may exert protective effects on NASH partially by modulating gut microbiota and correlated metabolites.

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Amelioration of hepatic steatosis by dietary essential amino acid-induced ubiquitination

Cited by 34 publications

References 61 publications

How the ends signal the end: Regulation by E3 ubiquitin ligases recognizing protein termini

How the ends signal the end: Regulation by E3 ubiquitin ligases recognizing protein termini

Metabolomics to identify fingerprints of carotid atherosclerosis in nonobese metabolic dysfunction-associated fatty liver disease

Lingguizhugan decoction improves non-alcoholic steatohepatitis partially by modulating gut microbiota and correlated metabolites

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