Integrated Multiomics Reveals Glucose Use Reprogramming and Identifies a Novel Hexokinase in Alcoholic Hepatitis

Massey, Veronica; Parrish, Austin; Argemí, Josepmaria; Arroyo, María Perla Moreno; Mello, Aline Haas de; Garcı́a-Rocha, Mar; Altamirano, José; Òdena, Gemma; Dubuquoy, Laurent; Louvet, Alexandre; Martinez, Carlos; Adrover, Anna; Affò, Silvia; Morales-Ibanez, Oriol; Sancho‐Bru, Pau; Millán, Cristina; Alvarado‐Tapias, Edilmar; Morales-Arráez, Dalia; Caballería, Juan; Mann, Jelena; Cao, Sheng; Sun, Zhaoli; Shah, Vijay H.; Cameron, Andrew M.; Mathurin, P.; Snider, Natasha T.; Villanueva, Càndid; Morgan, Timothy R.; Guinovart, Joan J.; Vadigepalli, Rajanikanth; Bataller, Ramón

doi:10.1053/j.gastro.2020.12.008

Cited by 45 publications

(47 citation statements)

References 32 publications

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“…Representative staining images are shown (figure 1F). Gene expression signature of IL-11-signalling in liver22 23 or monocytes24 showed a mild positive association with severity of AH (online supplemental figure 3).…”

Section: Resultsmentioning

confidence: 99%

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Interleukin-11 drives human and mouse alcohol-related liver disease

Effenberger

Widjaja

Grabherr

et al. 2022

Gut

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ObjectiveAlcoholic hepatitis (AH) reflects acute exacerbation of alcoholic liver disease (ALD) and is a growing healthcare burden worldwide. Interleukin-11 (IL-11) is a profibrotic, proinflammatory cytokine with increasingly recognised toxicities in parenchymal and epithelial cells. We explored IL-11 serum levels and their prognostic value in patients suffering from AH and cirrhosis of various aetiology and experimental ALD.DesignIL-11 serum concentration and tissue expression was determined in a cohort comprising 50 patients with AH, 110 patients with cirrhosis and 19 healthy volunteers. Findings were replicated in an independent patient cohort (n=186). Primary human hepatocytes exposed to ethanol were studied in vitro. Ethanol-fed wildtype mice were treated with a neutralising murine IL-11 receptor-antibody (anti-IL11RA) and examined for severity signs and markers of ALD.ResultsIL-11 serum concentration and hepatic expression increased with severity of liver disease, mostly pronounced in AH. In a multivariate Cox-regression, a serum level above 6.4 pg/mL was a model of end-stage liver disease independent risk factor for transplant-free survival in patients with compensated and decompensated cirrhosis. In mice, severity of alcohol-induced liver inflammation correlated with enhanced hepatic IL-11 and IL11RA expression. In vitro and in vivo, anti-IL11RA reduced pathogenic signalling pathways (extracellular signal-regulated kinases, c-Jun N-terminal kinase, NADPH oxidase 4) and protected hepatocytes and murine livers from ethanol-induced inflammation and injury.ConclusionPathogenic IL-11 signalling in hepatocytes plays a crucial role in the pathogenesis of ALD and could serve as an independent prognostic factor for transplant-free survival. Blocking IL-11 signalling might be a therapeutic option in human ALD, particularly AH.

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Section: Resultsmentioning

confidence: 99%

“…We carefully assessed the burden of the trial interventions on patients. Sample metadata for public cohorts Liu et al ,22 Massey et al 23 and Weichselbaum et al 24 were retrieved from GEO (GSE155907, GSE142530 and GSE135285, respectively). We intend to disseminate the main results to trial participants.…”

Section: Methodsmentioning

confidence: 99%

Interleukin-11 drives human and mouse alcohol-related liver disease

Effenberger

Widjaja

Grabherr

et al. 2022

Gut

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“…Alcoholic hepatitis is a disease characterized by hepatocyte de-differentiation and loss of hepatocyte regenerative capacity [20]. The ingredients from Chinese herbal have been proved to be a promising remedy for the treatment of liver injury [21].…”

Section: Discussionmentioning

confidence: 99%

The Integrated Analysis of Transcriptomics and Metabolomics Unveils the Therapeutical Effect of Asiatic Acid on Alcoholic Hepatitis in Rats

Chen

Huang

et al. 2022

Inflammation

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The present study was to investigate the therapeutical effects and mechanisms of Asiatic acid from Potentilla Chinensis against alcoholic hepatitis. Rats were intragastrically fed with alcohol for 12 weeks to induce alcoholic hepatitis and then treated with various drugs for further 12 weeks. The results showed that Asiatic acid signi cantly alleviated liver injury caused by alcohol in rats, as evidenced by the improved histological changes and the lower levels of AST, ALT, and TBIL. Besides, Asiatic acid signi cantly enhanced the activity of ADH and ALDH, promoting alcohol metabolism. Asiatic acid suppressed CYP2E1 activity and NADP + /NADPH ratio, resulting in low ROS production. Further study revealed that Asiatic acid markedly reduced hepatocyte apoptosis by regulating the expression levels of the caspase and Bcl-2 families. Moreover, Asiatic acid could regulate the Keap1/Nrf2 and NF-κB signaling pathway, attenuating oxidative stress and in ammation as a result. Interestingly, the comprehensive analysis of transcriptomics and metabolomics indicated that Asiatic acid regulated the gene expression of Gpat4 and thereby affected the biosynthesis of the metabolites (1-acyl-Sn-glycerol-3-phosphocholine, phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine), regulating the glycerophospholipid metabolism pathway and ultimately ameliorating hepatocyte damage. In conclusion, this study demonstrates that Asiatic acid can ameliorate alcoholic hepatitis by modulating the NF-κB and Keap1/Nrf2 signaling pathways and the glycerophospholipid metabolism pathway, which may be developed as a potential medicine for the treatment of alcoholic hepatitis.

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“…In addition, SAMTOR acts as the sensor for cellular S ‐adenosylmethionine (SAM) levels, and SAMTOR binds with GATOR1 and KICSTOR upon deprivation of methionine or SAM to inhibit mTORC1 (Gu, Orozco et al, 2017). In a recent metabolomics study using human alcoholic hepatitis (AH) liver samples, it was found that hepatic SAM levels in AH patient livers increased 4.6‐fold whereas the levels of leucine and arginine decreased compared with normal liver tissues (Massey, Parrish et al, 2021). Chronic EtOH administration depletes hepatic SAM in rodents (Lu & Mato, 2005; Purohit, Abdelmalek et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Trehalose activates hepatic transcription factor EB (TFEB) but fails to ameliorate alcohol‐impaired TFEB and liver injury in mice

Chao

Wang

Yang

et al. 2021

Alcoholism Clin & Exp Res

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Background Recent evidence demonstrates that alcohol activates the mechanistic target of rapamycin (mTOR) and impairs hepatic transcription factor EB (TFEB) reducing autophagy and contributing to alcohol‐induced liver injury. Trehalose, a disaccharide, activates TFEB and protects against diet‐induced nonalcoholic fatty liver disease in mice. The aim of the present study was to investigate whether trehalose would reverse the impairment of TFEB induced by alcohol and protect against alcohol‐induced liver injury. Methods Male C57BL/6J mice were subjected to chronic‐plus‐binge (Gao‐binge) alcohol feeding with and without trehalose supplementation. Some mice were also administrered Alda‐1, an aldehyde dehydrogenase 2 agonist. Results We found that Alda‐1 did not affect Gao‐binge alcohol‐induced mTOR activation and impaired TFEB in mouse livers. Trehalose increased TFEB nuclear translocation, elevated levels of LC3‐II and lysosomal proteins in mouse livers and cultured AML12 cells, confirming the activation of TFEB by trehalose. However, trehalose did not improve the impairment in TFEB induced by Gao‐binge alcohol. Both Alda‐1 and trehalose failed to protect against Gao‐binge alcohol‐induced steatosis and liver injury, based on the serum levels of alanine aminotransferase (ALT), histological analysis, and levels of hepatic triglyceride. Interestingly, trehalose increased expression of pro‐inflammatory genes in mouse macrophage RAW264.7 cells and slightly increased the infiltration of hepatic neutrophils and inflammatory cytokine gene expression in Gao‐binge alcohol‐fed mice livers. Conclusions Trehalose fails to improve the impaired TFEB induced by Gao‐binge alcohol and does not protect against alcohol‐induced liver injury.

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Integrated Multiomics Reveals Glucose Use Reprogramming and Identifies a Novel Hexokinase in Alcoholic Hepatitis

Cited by 45 publications

References 32 publications

Interleukin-11 drives human and mouse alcohol-related liver disease

Interleukin-11 drives human and mouse alcohol-related liver disease

The Integrated Analysis of Transcriptomics and Metabolomics Unveils the Therapeutical Effect of Asiatic Acid on Alcoholic Hepatitis in Rats

Trehalose activates hepatic transcription factor EB (TFEB) but fails to ameliorate alcohol‐impaired TFEB and liver injury in mice

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