Switching from Fatty Acid Oxidation to Glycolysis Improves the Outcome of Acute‐On‐Chronic Liver Failure

Yu, Zujiang; Li, Jingjing; Ren, Zhigang; Sun, Ranran; Zhou, Yang; Zhang, Qi; Wang, Qiongye; Cui, Guangying; Li, Juan; Li, Ang; Duan, Zhenfeng; Xu, Yuming; Wang, Zhichao; Yin, Peiyuan; Piao, Hulin; Lv, Jun; Liu, Xiaorui; Wang, Yanfang; Fang, Ming; Zhuang, Zhengping; Xu, Guowang; Kan, Quancheng

doi:10.1002/advs.201902996

Cited by 19 publications

(20 citation statements)

References 32 publications

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“…On the one hand, our study showed that the CS enzymatic activity in the Gansu zokor liver was significantly downregulated under the MH4w condition, and the same results occurred in its mRNA and protein expression. These results indicated that similar to previous studies ( 92 , 93 ), the long-term (4 weeks) moderate hypoxia would weaken the TCA cycle. Moreover, the above metabolite results showed that the levels of the TCA metabolites citrate and succinate were substantially reduced in the liver following MH4w hypoxia, which also provides evidence that the TCA cycle is inhibited under long-term (4 weeks) moderate hypoxia.…”

Section: Discussionsupporting

confidence: 91%

“…Under aerobic conditions, glucose is usually assumed to be fully burned by tissues through the TCA cycle ( 91 ). As evidenced by numerous studies, hypoxic conditions suppress the TCA cycle, such as it would occur in acute-on-chronic liver failure and cancer cells ( 92 , 93 ). Citrate synthase initiates the TCA cycle and plays a critical role in this metabolism pathway ( 43 , 94 ).…”

Section: Discussionmentioning

confidence: 99%

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Gut Microbiome Alterations and Hepatic Metabolic Flexibility in the Gansu Zokor, Eospalax cansus: Adaptation to Hypoxic Niches

Lin

Yang

Guo

et al. 2022

Front. Cardiovasc. Med.

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The Gansu zokor (Eospalax cansus), a typical subterranean rodent endemic to the Chinese Loess Plateau, spends almost its whole life in its self-constructed underground burrows and has strong adaptability to ambient hypoxia. Energy adaptation is the key to supporting hypoxia tolerance, and recent studies have shown that the intestinal microbiota has an evident effect on energy metabolism. However, how the gut microbiome of Gansu zokor will change in response to hypoxia and the metabolic role played by the microbiome have not been reported. Thus, we exposed Gansu zokors to severe hypoxia of 6.5% of O2 (6 or 44 h) or moderate hypoxia of 10.5% of O2 (44 h or 4 weeks), and then analyzed 16S rRNA sequencing, metagenomic sequencing, metagenomic binning, liver carbohydrate metabolites, and the related molecular levels. Our results showed that the hypoxia altered the microbiota composition of Gansu zokor, and the relative contribution of Ileibacterium to carbohydrate metabolism became increased under hypoxia, such as glycolysis and fructose metabolism. Furthermore, Gansu zokor liver enhanced carbohydrate metabolism under the short-term (6 or 44 h) hypoxia but it was suppressed under the long-term (4 weeks) hypoxia. Interestingly, under all hypoxia conditions, Gansu zokor liver exhibited enhanced fructose-driven metabolism through increased expression of the GLUT5 fructose transporter, ketohexokinase (KHK), aldolase B (ALDOB), and aldolase C (ALDOC), as well as increased KHK enzymatic activity and fructose utilization. Overall, our results suggest that the altered gut microbiota mediates the carbohydrate metabolic pattern under hypoxia, possibly contributing to the hepatic metabolic flexibility in Gansu zokor, which leads to better adaptation to hypoxic environments.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Gut Microbiome Alterations and Hepatic Metabolic Flexibility in the Gansu Zokor, Eospalax cansus: Adaptation to Hypoxic Niches

Lin

Yang

Guo

et al. 2022

Front. Cardiovasc. Med.

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“…Urea cycle dysregulation has been reported in some liver diseases and causes high mortality [ 8 , 9 , 25 ]. Accumulating studies suggested that urea cycle was crucial for liver injury through adaptive immune response regulation and highly toxic metabolic byproduct elimination [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

“…The urea cycle, which is exclusively located in the liver, the central organ for metabolism and detoxification, is a vital process involving 5 enzymes (Cps1, Otc, Ass1, Asl, and Arg1) that convert the highly toxic metabolic byproduct, ammonia, into urea, following amino acid metabolism [ 6 , 7 ]. Urea cycle dysregulation has been reported in some liver diseases and causes high mortality, such as in hepatitis B virus-related liver failure and nonalcoholic fatty liver disease [ 8 , 9 ]. Moreover, urea cycle-related amino acids arginine-ornithine homeostasis plays a crucial role for liver injury by adaptive immune response regulation [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Oridonin Alters Hepatic Urea Cycle via Gut Microbiota and Protects against Acetaminophen‐Induced Liver Injury

Hong

Liu

Chen

et al. 2021

Oxidative Medicine and Cellular Longevity

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Acetaminophen (APAP) hepatotoxicity is the leading cause of acute liver failure in the western world. Oridonin (OD), which is the major active ingredient of the traditional Chinese medicine Rabdosia rubescens, reportedly exerts anti-inflammatory and antioxidative effects. Here, we first find that OD protects against APAP-induced hepatotoxicity. The results of hepatic tissue-associated RNA-seq and metabolomics showed that the protective effects of OD were dependent upon urea cycle regulation. And such regulation of OD is gut microbiota partly dependent, as demonstrated by fecal microbiota transplantation (FMT). Furthermore, using 16S rRNA sequencing, we determined that OD significantly enriched intestinal Bacteroides vulgatus, which activated the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway to regulate redox homeostasis against APAP by urea cycle. In conclusion, our study suggests that the Bacteroides vulgatus-urea cycle-Nrf2 axis may be a potential target for reducing APAP-induced liver injury, which is altered by OD.

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“…In Asia, the main etiology of ACLF is chronic hepatitis B virus (HBV) infection ( 21 – 23 ). The purpose of our study was to provide new data on the treatment of HBV-related ACLF (HBV-ACLF) using G-CSF.…”

Section: Introductionmentioning

confidence: 99%

Granulocyte Colony-Stimulating Factor Accelerates the Recovery of Hepatitis B Virus-Related Acute-on-Chronic Liver Failure by Promoting M2-Like Transition of Monocytes

Tong

Wang

et al. 2022

Front. Immunol.

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Background and AimAcute-on-chronic liver failure (ACLF) has a high mortality rate. The role of granulocyte colony-stimulating factor (G-CSF) in ACLF remains controversial. Monocytes/macrophages are core immune cells, which are involved in the initiation and progression of liver failure; however, the effect of G-CSF on monocytes/macrophages is unclear. The study aimed to verify the clinical efficacy of G-CSF and explore the effect of it on monocytes in hepatitis B virus (HBV)-related ACLF (HBV-ACLF) paitents.MethodsWe performed a large randomized controlled clinical trial for the treatment of HBV-ACLF using G-CSF. A total of 111 patients with HBV-ACLF were prospectively randomized into the G-CSF group (5 μg/kg G-CSF every day for 6 days, then every other day until day 18) or the control group (standard therapy). All participants were followed up for at least 180 days. The relationship between monocyte count and mortality risk was analyzed. The effect of G-CSF on the phenotype and function of monocytes from patients with HBV-ACLF was evaluated using flow cytometry in vivo and in vitro experiments.ResultsThe survival probability of the G-CSF group at 180 days was higher than that of the control group (72.2% vs. 53.8%, P = 0.0142). In the G-CSF-treated group, the monocyte counts on days 0 and 7 were independently associated with an evaluated mortality risk in the fully adjusted model (Model 3) [at day 0: hazard ratio (HR) 95% confidence interval (CI): 15.48 (3.60, 66.66), P = 0.0002; at day 7: HR (95% CI): 1.10 (0.50, 2.43), P=0.8080]. Further analysis showed that after treatment with G-CSF in HBV-ACLF patients, the expression of M1-like markers (HLA-DR and CD86) in monocytes decreased (HLA-DR: P = 0.0148; CD86: P = 0.0764). The expression of MerTK (M2-like marker) increased (P = 0.0002). The secretion of TNF-α, IL-6, and IL-10 from monocytes decreased without lipopolysaccharide (LPS) stimulation (TNF-α: P < 0.0001; IL-6: P= 0.0025; IL-10: P = 0.0004) or with LPS stimulation (TNF-α: P = 0.0439; P = 0.0611; IL-10: P = 0.0099). Similar effects were observed in vitro experiments.ConclusionG-CSF therapy confers a survival benefit to patients with HBV-ACLF. G-CSF can promote the anti-inflammatory/pro-restorative phenotype (M2-like) transition of monocytes, which may contribute to the recovery of ACLF.Clinical Trial Registration NumberClinicalTrials.gov, identifier (NCT02331745).

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Switching from Fatty Acid Oxidation to Glycolysis Improves the Outcome of Acute‐On‐Chronic Liver Failure

Cited by 19 publications

References 32 publications

Gut Microbiome Alterations and Hepatic Metabolic Flexibility in the Gansu Zokor, Eospalax cansus: Adaptation to Hypoxic Niches

Gut Microbiome Alterations and Hepatic Metabolic Flexibility in the Gansu Zokor, Eospalax cansus: Adaptation to Hypoxic Niches

Oridonin Alters Hepatic Urea Cycle via Gut Microbiota and Protects against Acetaminophen‐Induced Liver Injury

Granulocyte Colony-Stimulating Factor Accelerates the Recovery of Hepatitis B Virus-Related Acute-on-Chronic Liver Failure by Promoting M2-Like Transition of Monocytes

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