bims-liverm Biomed News
on Liver Metabolism
Issue of 2023–04–23
eight papers selected by
  1. RIPK3 promoter hypermethylation in hepatocytes protects from bile acid-induced inflammation and necroptosis.
  2. Phosphatidylglucose Alleviates Atherosclerosis by Increasing Cholesterol Alienation to Bile Acids and Cholesterol Efflux in ApoE-/- Mice.
  3. G-protein coupled receptor 19 (GPR19) knockout mice display sex-dependent metabolic dysfunction.
  4. Farnesoid X receptor is inhibited after ileum transposition in diabetic rats: its hypoglycemic effect.
  5. Metabolic alterations of the gut-liver axis induced by cholic acid contribute to hepatic steatosis in rats.
  6. Predictive value of bile acids as metabolite biomarkers for gallstones: A protocol of systematic review and meta-analysis.
  7. Normalization of hepatic ChREBP activity does not protect against liver disease progression in a mouse model for Glycogen Storage Disease type Ia.
  8. Conjugated bile acids are nutritionally re-programmable antihypertensive metabolites.
  1. Cell Death Dis. 2023 Apr 18. 14(4): 275
    RIPK3 promoter hypermethylation in hepatocytes protects from bile acid-induced inflammation and necroptosis.
    Jessica Hoff, Ling Xiong, Tobias Kammann, Sophie Neugebauer, Julia M Micheel, Nikolaus Gaßler, Michael Bauer, Adrian T Press.
      Necroptosis facilitates cell death in a controlled manner and is employed by many cell types following injury. It plays a significant role in various liver diseases, albeit the cell-type-specific regulation of necroptosis in the liver and especially hepatocytes, has not yet been conceptualized. We demonstrate that DNA methylation suppresses RIPK3 expression in human hepatocytes and HepG2 cells. In diseases leading to cholestasis, the RIPK3 expression is induced in mice and humans in a cell-type-specific manner. Overexpression of RIPK3 in HepG2 cells leads to RIPK3 activation by phosphorylation and cell death, further modulated by different bile acids. Additionally, bile acids and RIPK3 activation further facilitate JNK phosphorylation, IL-8 expression, and its release. This suggests that hepatocytes suppress RIPK3 expression to protect themselves from necroptosis and cytokine release induced by bile acid and RIPK3. In chronic liver diseases associated with cholestasis, induction of RIPK3 expression may be an early event signaling danger and repair through releasing IL-8.
    DOI:  https://doi.org/10.1038/s41419-023-05794-0
  2. J Sci Food Agric. 2023 Apr 17.
    Phosphatidylglucose Alleviates Atherosclerosis by Increasing Cholesterol Alienation to Bile Acids and Cholesterol Efflux in ApoE-/- Mice.
    Jin-Yue Yang, Tian-Tian Zhang, Zhu-Lin Yu, Xiao-Yue Li, Ying-Cai Zhao, Xiang-Zhao Mao, Yu-Ming Wang, Chang-Hu Xue.
       BACKGROUND: Phosphatidylcholine (PC) are considered to be the major dietary sources for choline, which is associated with the atherosclerosis progress. Thus, phosphatidylglucose (PG) was prepared by enzymatic modification of PC to study the effects on atherosclerosis in apolipoprotein E deficient (ApoE-/- ) mice, and to investigate its dose response relationship.
    RESULTS: The results showed that dietary PG significantly decreased the atherosclerotic lesion area in a dose dependent manner. Further studies found that the intervention of 0.8 g kg-1 diet and 2 g kg-1 diet PG for 4 mon significantly decreased free cholesterol level and thus reduced the total cholesterol level in serum. The results of cholesterol distribution among lipoproteins showed that dietary PG significantly decreased low-density lipoprotein level in ApoE-/- mice. In addition, only administration of high-dose PG significantly reduced the total cholesterol levels in liver tissues by 31.2%. Furthermore, mice treated with high-dose PG had an expanded bile acid pool and increased the ratio of conjugated bile acids to unconjugated bile acids in liver, serum and gallbladder via increasing hepatic gene expression of primary and conjugated bile acid synthesis. Additionally, low-dose and high-dose PG significantly increased total fecal sterols by 20.8% and 11.9%, respectively, by increasing sitosterol and ethylcoprostanol levels.
    CONCLUSION: These results indicate that PG alleviated atherosclerosis in a dose dependent manner via increasing cholesterol alienation to bile acids and cholesterol efflux. This article is protected by copyright. All rights reserved.
    Keywords:  atherosclerosis; bile acid; cholesterol; fecal sterols; phosphatidylglucose
    DOI:  https://doi.org/10.1002/jsfa.12626
  3. Sci Rep. 2023 Apr 15. 13(1): 6134
    G-protein coupled receptor 19 (GPR19) knockout mice display sex-dependent metabolic dysfunction.
    Bellina A S Mushala, Bingxian Xie, Ian J Sipula, Michael W Stoner, Dharendra Thapa, Janet R Manning, Paramesha Bugga, Amber M Vandevender, Michael J Jurczak, Iain Scott.
      G-protein coupled receptors (GPCRs) mediate signal transduction from the cellular surface to intracellular metabolic pathways. While the function of many GPCRs has been delineated previously, a significant number require further characterization to elucidate their cellular function. G-protein coupled receptor 19 (GPR19) is a poorly characterized class A GPCR which has been implicated in the regulation of circadian rhythm, tumor metastasis, and mitochondrial homeostasis. In this report, we use a novel knockout (KO) mouse model to examine the role of GPR19 in whole-body metabolic regulation. We show that loss of GPR19 promotes increased energy expenditure and decreased activity in both male and female mice. However, only male GPR19 KO mice display glucose intolerance in response to a high fat diet. Loss of GPR19 expression in male mice, but not female mice, resulted in diet-induced hepatomegaly, which was associated with decreased expression of key fatty acid oxidation genes in male GPR19 KO livers. Overall, our data suggest that loss of GPR19 impacts whole-body energy metabolism in diet-induced obese mice in a sex-dependent manner.
    DOI:  https://doi.org/10.1038/s41598-023-33308-7
  4. Int J Med Sci. 2023 ;20(5): 595-605
    Farnesoid X receptor is inhibited after ileum transposition in diabetic rats: its hypoglycemic effect.
    Weijie Chen, Shengnan Zhou, Jianchun Xiao, Wei Liu, Qiang Qu, Xiaodong He.
      Background: Aim to investigate bile acid profile changes and the Farnesoid X receptor (FXR) status after ileotransposition (IT), and reveal its possible hypoglycemic mechanism. Methods: Twenty male diabetic rats were randomly assigned into the IT group and the sham IT (SH) group. Bile acid profiles were measured using an ultra-performance liquid chromatography-tandem mass spectrometry. Glucose metabolism was monitored after oral administration of FXR inhibitor and agonist. And the expression of key FXR target genes were measured. Results: The levels of β-muricholic acid (P = 0.047), tauro-α-muricholic acid and tauro-β-muricholic acid (P < 0.001) in plasma in the IT group were higher than those in the SH group, and the levels of taurocholic acid (P = 0.049) and turoursodeoxycholic acid (P = 0.030) were lower than those in the SH group. After inhibition of intestinal FXR, the glucose metabolism in the SH group was improved. When FXR agonist was given, the blood glucose level was increased in both groups. After sacrifice, the levels of glycoursodeoxycholic acid, tauro-α-muricholic acid and tauro-β-muricholic acid in liver and ileum tissues were higher than those in the SH group (P < 0.05), the level of α- muricholic acid (P < 0.001) in liver tissues were lower than that in the SH group. Moreover, the expression of CYP7A1 mRNA (P < 0.001) and FGF15 mRNA (P = 0.001) in the IT group was significantly higher, and the expression of PEPCK mRNA (P = 0.004), SREPB1c mRNA (P = 0.005) and SRB1 mRNA (P = 0.001) were significantly lower than that in the SH group. Conclusions: We demonstrate a remarkable heterogeneity of BA profiles after IT, FXR activation might has a detrimental effect on glucose metabolism.
    Keywords:  bile acids and salts; diabetes mellitus; farnesoid X receptor; glucose; ileum
    DOI:  https://doi.org/10.7150/ijms.80563
  5. Biochim Biophys Acta Mol Cell Biol Lipids. 2023 Apr 17. pii: S1388-1981(23)00043-4. [Epub ahead of print] 159319
    Metabolic alterations of the gut-liver axis induced by cholic acid contribute to hepatic steatosis in rats.
    Hongxia Liu, Fumika Yokoyama, Satoshi Ishizuka.
      12α-Hydroxylated (12αOH) bile acids (BAs) selectively increase with high-fat diet intake. Dietary supplementation with cholic acid (CA) in rats is a possible strategy to reveal the causal link between 12αOH BAs and hepatic steatosis. The present study aimed to investigate the metabolic mechanism underlying the effect of 12αOH BAs on hepatic steatosis. Male WKAH rats were fed either a control (Ct) or CA-supplemented diet (0.5 g/kg). After the 12-week intervention, the CA diet elevated the 12αOH BA levels in the gut-liver axis. CA-fed rats showed greater hepatic lipid accumulation than in the Ct group, regardless of the dietary energy balance. Untargeted metabolomics suggested marked differences in the fecal metabolome of rats subjected to the CA diet compared with that of Ct, characterized by the depletion of fatty acids and enrichment of amino acids and amines. Moreover, the liver metabolome differed in the CA diet group, characterized by an alteration in redox-related pathways. The CA diet elevated nicotinamide adenine dinucleotide consumption owing to the activation of poly(ADP-ribose) polymerase 1, resulting in impaired peroxisome proliferator-activated receptor α signaling in the liver. The CA diet increased sedoheptulose 7-phosphate, and enhanced glucose-6-phosphate dehydrogenase activity, suggesting promotion of the pentose phosphate pathway that generates reducing equivalents. Integrated analysis of the gut-liver metabolomic data revealed the role of deoxycholic acid and its liver counterpart in mediating these metabolic alterations. These observations suggest that alterations in metabolites induced by 12αOH BAs in the gut-liver axis contribute to the enhancement of liver lipid accumulation.
    Keywords:  Bile acid; Fecal metabolites; Hepatic steatosis; Metabolomics; Redox
    DOI:  https://doi.org/10.1016/j.bbalip.2023.159319
  6. PLoS One. 2023 ;18(4): e0284138
    Predictive value of bile acids as metabolite biomarkers for gallstones: A protocol of systematic review and meta-analysis.
    Xu Han, Juan Wang, Yingnan Wu, Hao Gu, Ning Zhao, Xing Liao, Miao Jiang.
       BACKGROUND: Plenty of studies have focused on the bile acids profile in gallstones. The objective of our systematic review is to provide a comprehensive summary about bile acids profiles in gallstones and analyzes the difference between gallstones and control group in diverse samples, determining the characteristic bile acids as the metabolite biomarkers for predicting gallstone.
    METHODS: EMBASE, the Cochrane Library, PubMed, Web of Science, Wanfang databases, China National Knowledge Infrastructure (CNKI), VIP Information Resource Integration Service Platform (CQVIP), and China Biology Medicine Disc (SinoMed) will be searched with the keywords of gallstones and metabolomics. The screening process will be performed strictly according to inclusion and exclusion criteria. The CONSORT checklist and the Newcastle-Ottawa Scale (NOS) will assess the risk of bias for randomized controlled trials and observational studies, respectively. The qualitative review will be conducted to summarize the bile acids profile in gallstones. The concentrations of bile acids in both case group and control group will be the primary outcomes to perform the meta-analyses.
    EXPECTED RESULTS: Our systematic review will find the characteristic bile acids as the candidate metabolite biomarkers which equipped potential value to predict gallstones.
    CONCLUSION: Expanding the current knowledge on the physiopathology of gallstones and identifying novel predictive biomarkers can help to facilitate the detection and management of gallstones. Consequently, we expect this protocol to be a reasonable method to filtrate candidate differential bile acids which have potential value to predict gallstones.
    PROSPERO REGISTRATION NUMBER: CRD42022339649.
    DOI:  https://doi.org/10.1371/journal.pone.0284138
  7. Cancer Metab. 2023 Apr 21. 11(1): 5
    Normalization of hepatic ChREBP activity does not protect against liver disease progression in a mouse model for Glycogen Storage Disease type Ia.
    Martijn G S Rutten, Yu Lei, Joanne H Hoogerland, Vincent W Bloks, Hong Yang, Trijnie Bos, Kishore A Krishnamurthy, Aycha Bleeker, Mirjam H Koster, Rachel E Thomas, Justina C Wolters, Hilda van den Bos, Gilles Mithieux, Fabienne Rajas, Adil Mardinoglu, Diana C J Spierings, Alain de Bruin, Bart van de Sluis, Maaike H Oosterveer.
       BACKGROUND: Glycogen storage disease type 1a (GSD Ia) is an inborn error of metabolism caused by a defect in glucose-6-phosphatase (G6PC1) activity, which induces severe hepatomegaly and increases the risk for liver cancer. Hepatic GSD Ia is characterized by constitutive activation of Carbohydrate Response Element Binding Protein (ChREBP), a glucose-sensitive transcription factor. Previously, we showed that ChREBP activation limits non-alcoholic fatty liver disease (NAFLD) in hepatic GSD Ia. As ChREBP has been proposed as a pro-oncogenic molecular switch that supports tumour progression, we hypothesized that ChREBP normalization protects against liver disease progression in hepatic GSD Ia.
    METHODS: Hepatocyte-specific G6pc knockout (L-G6pc-/-) mice were treated with AAV-shChREBP to normalize hepatic ChREBP activity.
    RESULTS: Hepatic ChREBP normalization in GSD Ia mice induced dysplastic liver growth, massively increased hepatocyte size, and was associated with increased hepatic inflammation. Furthermore, nuclear levels of the oncoprotein Yes Associated Protein (YAP) were increased and its transcriptional targets were induced in ChREBP-normalized GSD Ia mice. Hepatic ChREBP normalization furthermore induced DNA damage and mitotic activity in GSD Ia mice, while gene signatures of chromosomal instability, the cytosolic DNA-sensing cGAS-STING pathway, senescence, and hepatocyte dedifferentiation emerged.
    CONCLUSIONS: In conclusion, our findings indicate that ChREBP activity limits hepatomegaly while decelerating liver disease progression and protecting against chromosomal instability in hepatic GSD Ia. These results disqualify ChREBP as a therapeutic target for treatment of liver disease in GSD Ia. In addition, they underline the importance of establishing the context-specific roles of hepatic ChREBP to define its therapeutic potential to prevent or treat advanced liver disease.
    Keywords:  Carbohydrate Response Element Binding Protein; Cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING); Glycogen Storage Disease type 1a; Hepatomegaly; Yes Associated Protein
    DOI:  https://doi.org/10.1186/s40170-023-00305-3
  8. J Hypertens. 2023 Apr 06.
    Conjugated bile acids are nutritionally re-programmable antihypertensive metabolites.
    Saroj Chakraborty, Anju Lulla, Xi Cheng, Ji-Youn Yeo, Juthika Mandal, Tao Yang, Xue Mei, Piu Saha, Rachel M Golonka, Beng San Yeoh, Blair Mell, Wei Jia, Vasanta Putluri, Danthasinghe Waduge Badrajee Piyarathna, Nagireddy Putluri, Arun Sreekumar, Katie Meyer, Matam Vijay-Kumar, Bina Joe.
       BACKGROUND: Hypertension is the largest risk factor affecting global mortality. Despite available medications, uncontrolled hypertension is on the rise, whereby there is an urgent need to develop novel and sustainable therapeutics. Because gut microbiota is now recognized as an important entity in blood pressure regulation, one such new avenue is to target the gut-liver axis wherein metabolites are transacted via host-microbiota interactions. Knowledge on which metabolites within the gut-liver axis regulate blood pressure is largely unknown.
    METHOD: To address this, we analyzed bile acid profiles of both human and hypertensive rat models and report that conjugated bile acids are inversely correlated with blood pressure in humans and rats.
    RESULTS: Notably intervening with taurine rescued bile acid conjugation and reduced blood pressure in hypertensive rats. Subsequently, untargeted metabolomics uncovered lower energy metabolism following conjugation of bile acids as a mechanism alleviating high blood pressure.
    CONCLUSION: Together this work reveals conjugated bile acids as nutritionally re-programmable anti-hypertensive metabolites.
    GRAPHICAL ABSTRACT: http://links.lww.com/HJH/C165.
    DOI:  https://doi.org/10.1097/HJH.0000000000003423
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