bims-liverm Biomed News
on Liver Metabolism
Issue of 2023–03–19
eleven papers selected by
  1. The role of bile acids in regulating glucose and lipid metabolism.
  2. Bile acid increase during bulevirtide treatment of hepatitis D is not associated with a decline in HDV RNA.
  3. Protective potential of the gallbladder in primary sclerosing cholangitis.
  4. A simple and rapid LC-MS/MS method for the simultaneous determination of 15 bile acids in human serum and its application to patients with decompensated cirrhosis.
  5. Bile salt hydrolases shape the bile acid landscape and restrict Clostridioides difficile growth in the murine gut.
  6. Serum Bile Acid Metabolites Predict the Therapeutic Effect of Mesalazine in Patients with Ulcerative Colitis.
  7. Revisiting the role of glucagon in health, diabetes mellitus and other metabolic diseases.
  8. New insights into the inter-organ crosstalk mediated by ChREBP.
  9. Persistent fasting lipogenesis links impaired ketogenesis with citrate synthesis in humans with non-alcoholic fatty liver.
  10. Antimicrobial protein REG3A regulates glucose homeostasis and insulin resistance in obese diabetic mice.
  11. Effects of black raspberry extract on gut microbiota, microbial metabolites, and expressions of the genes involved in cholesterol and bile acid metabolisms in rats fed excessive choline with a high-fat diet.
  1. Endocr J. 2023 Mar 15.
    The role of bile acids in regulating glucose and lipid metabolism.
    Hengcai Yu, Ruifang Nie, Chengwu Shen.
      In recent years, bile acids (BAs) are increasingly being appreciated as signaling molecules beyond their involvement in bile formation and fat absorption. The farnesoid X receptor (FXR) and the G protein-coupled bile acid receptor 1 (GPBAR1, also known as TGR5) are two dominating receptors through which BAs modulate glucose and lipid metabolism. FXR is highly expressed in the intestine and liver. GPBAR1 is highly expressed in the intestine. The present study reviews the metabolism and regulation of BAs, especially the effects of BAs on glucose and lipid metabolism by acting on FXR in the liver and intestine, and GPBAR1 in the intestine. Furthermore, it explains that fibroblast growth factor 15/19 (FGF15/19), ceramide, and glucagon like peptide-1 (GLP-1) are all involved in the signaling pathways by which BAs regulate glucose and lipid metabolism. This article aims to provide an overview of the molecular mechanisms by which BAs regulate glucose and lipid metabolism, and promote further scientific and clinical research on BAs.
    Keywords:  Bile acids; Farnesoid X receptor; G protein-coupled bile acid receptor 1; Glucose and lipid metabolism; Intestine
    DOI:  https://doi.org/10.1507/endocrj.EJ22-0544
  2. J Viral Hepat. 2023 Mar 16.
    Bile acid increase during bulevirtide treatment of hepatitis D is not associated with a decline in HDV RNA.
    Katja Deterding, Cheng-Jian Xu, Kerstin Port, Christopher Dietz-Fricke, Xun Jiang, Benjamin Maasoumy, Markus Cornberg, Heiner Wedemeyer.
       BACKGROUND & AIM: Bulevirtide (BLV) is an entry inhibitor blocking entry of HBsAg into hepatocytes by interfering with the bile acid transporter Na+-taurocholate co-transporting polypeptide. We here investigated if bile acid levels before or during BLV treatment would correlate with HDV RNA declines.
    METHODS: We studied 20 patients with compensated HDV infection receiving a daily dose of 2 mg bulevirtide subcutaneously qd for at least 24 weeks.
    RESULTS: ALT levels improved in all patients including 13/20 patients showing normal ALT values at treatment week 24. An HDV RNA drop of at least 50% was evident in 20/20 patients at week 24 including 10 patients showing a ≥ 2 log HDV RNA decline. Elevated bile acid levels were detected already before treatment in 10 patients and further increased during BLV administration with different kinetics. Baseline bile acids were associated with higher transient elastography values (p=0.0029) and evidence of portal hypertension (p=0.0004). Bile acid levels before treatment were associated with HDV RNA declines throughout therapy, but not at week 24 (rho= -0.577; p=0.0078; rho= -0.635, p=0.0026; rho= -0.577, p= 0.0077; rho= -0.519, p=0.0191; rho= -0.564, p=0.0119 and rho=-0.393, p=0.087 at treatment weeks 2, 8, 12, 16,20 and 24, respectively). However, bile acid increases during treatment were not associated with HDV RNA or ALT declines at any of the time points.
    CONCLUSIONS: BLV-induced increases in bile salts do not correlate with HDV RNA declines suggesting that the inhibitory effects of BLV on NTCP differ between blocking bile acid transport and hindering HBsAg entry. If baseline bile salt levels could be useful to predict virological response remains to be confirmed.
    Keywords:  HDV RNA; Hepatitis Delta; antiviral treatment; bile acids; bulevirtide
    DOI:  https://doi.org/10.1111/jvh.13831
  3. JHEP Rep. 2023 Apr;5(4): 100649
    Protective potential of the gallbladder in primary sclerosing cholangitis.
    Nora Cazzagon, Ester Gonzalez-Sanchez, Haquima El-Mourabit, Dominique Wendum, Dominique Rainteau, Lydie Humbert, Christophe Corpechot, Olivier Chazouillères, Lionel Arrivé, Chantal Housset, Sara Lemoinne.
       Background & Aims: Gallbladder enlargement is common in patients with primary sclerosing cholangitis (PSC). The gallbladder may confer hepatoprotection against bile acid overload, through the sequestration and cholecystohepatic shunt of bile acids. The aim of this study was to assess the potential impact of the gallbladder on disease features and bile acid homeostasis in PSC.
    Methods: Patients with PSC from a single tertiary center who underwent liver MRI with three-dimensional cholangiography and concomitant analyses of serum bile acids were included. Gallbladder volume was measured by MRI and a cut-off of 50 ml was used to define gallbladder enlargement. Bile acid profiles and PSC severity, as assessed by blood tests and MRI features, were compared among patients according to gallbladder size (enlarged vs. normal-sized) or presence (removed vs. conserved). The impact of cholecystectomy was also assessed in the Abcb4 knockout mouse model of PSC.
    Results: Sixty-one patients with PSC, all treated with ursodeoxycholic acid (UDCA), were included. The gallbladder was enlarged in 30 patients, whereas 11 patients had been previously cholecystectomized. Patients with enlarged gallbladders had significantly lower alkaline phosphatase, a lower tauro-vs. glycoconjugate ratio and a higher UDCA vs. total bile acid ratio compared to those with normal-sized gallbladders. In addition, gallbladder volume negatively correlated with the hydrophobicity index of bile acids. Cholecystectomized patients displayed significantly higher aspartate aminotransferase and more severe bile duct strictures and dilatations compared to those with conserved gallbladder. In the Abcb4 knockout mice, cholecystectomy caused an increase in hepatic bile acid content and in circulating secondary bile acids, and an aggravation in cholangitis, inflammation and liver fibrosis.
    Conclusion: Altogether, our findings indicate that the gallbladder fulfills protective functions in PSC.
    Impact and implications: In patients with primary sclerosing cholangitis (PSC), gallbladder status impacts on bile acid homeostasis and disease features. We found evidence of lessened bile acid toxicity in patients with PSC and enlarged gallbladders and of increased disease severity in those who were previously cholecystectomized. In the Abcb4 knockout mouse model of PSC, cholecystectomy causes an aggravation of cholangitis and liver fibrosis. Overall, our results suggest that the gallbladder plays a protective role in PSC.
    Keywords:  ABC, ATP-binding cassette transporter; Abcb4 knockout mice; BA, bile acid; Bile acids; C4, 7α-hydroxy-4-cholesten-3-one; CFTR, cystic fibrosis transmembrane conductance regulator; CK19, cytokeratin 19; Cholecystectomy; FGF19, fibroblast growth factor 19; Gallbladder volume; HPLC-MS/MS, high-performance liquid chromatography coupled to tandem mass spectrometry; IBD, inflammatory bowel disease; MRC, magnetic resonance cholangiography; Magnetic resonance imaging; PSC, primary sclerosing cholangitis; UDCA, ursodeoxycholic acid; ULN, upper limit of normal
    DOI:  https://doi.org/10.1016/j.jhepr.2022.100649
  4. Biomed Chromatogr. 2023 Mar 15. e5625
    A simple and rapid LC-MS/MS method for the simultaneous determination of 15 bile acids in human serum and its application to patients with decompensated cirrhosis.
    Ying Li, Li Cui, Mingli Liu, Furong Zhao, Hongzhi Sun.
      Liver cirrhosis is currently the twelfth leading cause of death globally and the sixth leading cause of death in China. Its treatment is expensive. Changes in the composition of the serum bile acid pool are sensitive indicators of the severity of liver cirrhosis. In this study, a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and used to simultaneously determine 15 bile acids in human serum in patients with decompensated cirrhosis. Sample preparation involved spiking with isotope internal standards (ISs) followed by protein precipitation and the analytical run time was 5 min. The LC-MS/MS method was fully validated according to CLSI C62A and the Consensus of method development and validation of liquid chromatography-tandem mass spectrometry in clinical laboratories. The method achieved an acceptable coefficient of variation for precision (0.83-14.80%) and accuracy (89.39-107.62%). Finally, as proof of applicability, the method was applied to patients with decompensated cirrhosis in routine clinical sample analysis. The degree of variation of different bile acids was clearly shown. These results indicated that abnormal metabolic pathways might play important roles in decompensated cirrhosis.
    Keywords:  LC-MS/MS; bile acids; decompensated cirrhosis; human serum
    DOI:  https://doi.org/10.1002/bmc.5625
  5. Nat Microbiol. 2023 Mar 13.
    Bile salt hydrolases shape the bile acid landscape and restrict Clostridioides difficile growth in the murine gut.
    Matthew H Foley, Morgan E Walker, Allison K Stewart, Sarah O'Flaherty, Emily C Gentry, Shakshi Patel, Violet V Beaty, Garrison Allen, Meichen Pan, Joshua B Simpson, Caroline Perkins, Molly E Vanhoy, Michael K Dougherty, Sarah K McGill, Ajay S Gulati, Pieter C Dorrestein, Erin S Baker, Matthew R Redinbo, Rodolphe Barrangou, Casey M Theriot.
      Bile acids (BAs) mediate the crosstalk between human and microbial cells and influence diseases including Clostridioides difficile infection (CDI). While bile salt hydrolases (BSHs) shape the BA pool by deconjugating conjugated BAs, the basis for their substrate selectivity and impact on C. difficile remain elusive. Here we survey the diversity of BSHs in the gut commensals Lactobacillaceae, which are commonly used as probiotics, and other members of the human gut microbiome. We structurally pinpoint a loop that predicts BSH preferences for either glycine or taurine substrates. BSHs with varying specificities were shown to restrict C. difficile spore germination and growth in vitro and colonization in pre-clinical in vivo models of CDI. Furthermore, BSHs reshape the pool of microbial conjugated bile acids (MCBAs) in the murine gut, and these MCBAs can further restrict C. difficile virulence in vitro. The recognition of conjugated BAs by BSHs defines the resulting BA pool, including the expansive MCBAs. This work provides insights into the structural basis of BSH mechanisms that shape the BA landscape and promote colonization resistance against C. difficile.
    DOI:  https://doi.org/10.1038/s41564-023-01337-7
  6. J Proteome Res. 2023 Mar 15.
    Serum Bile Acid Metabolites Predict the Therapeutic Effect of Mesalazine in Patients with Ulcerative Colitis.
    Qiaoli Sun, Yingjue Tang, Liang Dai, Zhipeng Tang, Wenjun Zhou, Tao Wu, Guang Ji.
      Ulcerative colitis (UC) is a systematic chronic disease characterized by insufficient intestinal absorption, and mesalazine is a common medical treatment. In the present study, 20 normal healthy controls (NC group), 10 unmedicated UC patients (UC group), and 20 mesalazine-responsive and 20 mesalazine-nonresponsive UC patients were recruited. A total of 42 serum BA metabolites, including 8 primary bile acids and 34 secondary bile acids (SBAs), were quantitatively measured. Compared with the NC group, serum SBAs in the UC patients were significantly lower but increased after mesalazine therapy. Differences in the serum TDCA, DCA, GDCA-3S, 12-keto LCA, and GCDCA-3S metabolites were found between the UC and NC groups, with AUC values of 0.777, 0.800, 0.815, 0.775, and 0.740, respectively. Furthermore, we identified 12-keto LCA as a specific BA marker of UC and BA biomarkers of mesalazine responsiveness. It was concluded that serum SBAs were decreased in UC patients, and TDCA, DCA, GDCA-3S, 12-keto LCA, and GCDCA-3S might aid in the diagnosis of UC. The abundance of SBAs increased after the mesalazine therapy, and serum 12-keto LCA was identified as an alternative invasive biomarker associated with UC diagnosis and therapeutic response, thereby providing a new approach for the prediction of response to mesalazine therapy in UC patients.
    Keywords:  bile acid; mesalazine; metabolomics; primary bile acid; secondary bile acid; ulcerative colitis
    DOI:  https://doi.org/10.1021/acs.jproteome.2c00820
  7. Nat Rev Endocrinol. 2023 Mar 17.
    Revisiting the role of glucagon in health, diabetes mellitus and other metabolic diseases.
    Sofie Hædersdal, Andreas Andersen, Filip K Knop, Tina Vilsbøll.
      Insulin and glucagon exert opposing effects on glucose metabolism and, consequently, pancreatic islet β-cells and α-cells are considered functional antagonists. The intra-islet hypothesis has previously dominated the understanding of glucagon secretion, stating that insulin acts to inhibit the release of glucagon. By contrast, glucagon is a potent stimulator of insulin secretion and has been used to test β-cell function. Over the past decade, α-cells have received increasing attention due to their ability to stimulate insulin secretion from neighbouring β-cells, and α-cell-β-cell crosstalk has proven central for glucose homeostasis in vivo. Glucagon is not only the counter-regulatory hormone to insulin in glucose metabolism but also glucagon secretion is more susceptible to changes in the plasma concentration of certain amino acids than to changes in plasma concentrations of glucose. Thus, the actions of glucagon also include a central role in amino acid turnover and hepatic fat oxidation. This Review provides insights into glucagon secretion, with a focus on the local paracrine actions on glucagon and the importance of α-cell-β-cell crosstalk. We focus on dysregulated glucagon secretion in obesity, non-alcoholic fatty liver disease and type 2 diabetes mellitus. Lastly, the future potential of targeting hyperglucagonaemia and applying dual and triple receptor agonists with glucagon receptor-activating properties in combination with incretin hormone receptor agonism is discussed.
    DOI:  https://doi.org/10.1038/s41574-023-00817-4
  8. Front Endocrinol (Lausanne). 2023 ;14 1095440
    New insights into the inter-organ crosstalk mediated by ChREBP.
    Thais Carbinatti, Marion Régnier, Lucia Parlati, Fadila Benhamed, Catherine Postic.
      Carbohydrate response element binding protein (ChREBP) is a glucose responsive transcription factor recognized by its critical role in the transcriptional control of glycolysis and de novo lipogenesis. Substantial advances in the field have revealed novel ChREBP functions. Indeed, due to its actions in different tissues, ChREBP modulates the inter-organ communication through secretion of peptides and lipid factors, ensuring metabolic homeostasis. Dysregulation of these orchestrated interactions is associated with development of metabolic diseases such as type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD). Here, we recapitulate the current knowledge about ChREBP-mediated inter-organ crosstalk through secreted factors and its physiological implications. As the liver is considered a crucial endocrine organ, we will focus in this review on the role of ChREBP-regulated hepatokines. Lastly, we will discuss the involvement of ChREBP in the progression of metabolic pathologies, as well as how the impairment of ChREBP-dependent signaling factors contributes to the onset of such diseases.
    Keywords:  ChREBP; hepatokines; inter-organ crosstalk; metabolic diseases; metabolism
    DOI:  https://doi.org/10.3389/fendo.2023.1095440
  9. J Clin Invest. 2023 Mar 16. pii: e167442. [Epub ahead of print]
    Persistent fasting lipogenesis links impaired ketogenesis with citrate synthesis in humans with non-alcoholic fatty liver.
    Xiaorong Fu, Justin A Fletcher, Stanisław Deja, Melissa Inigo-Vollmer, Shawn C Burgess, Jeffrey D Browning.
       BACKGROUND: Hepatic de novo lipogenesis (DNL) and β-oxidation are tightly coordinated, and their dysregulation is thought to contribute to the pathogenesis of non-alcoholic fatty liver (NAFL). Fasting normally relaxes DNL-mediated inhibition of hepatic β-oxidation, dramatically increasing ketogenesis and decreasing reliance on the TCA cycle. Thus, we tested whether aberrant oxidative metabolism in fasting NAFL subjects is related to the inability to halt fasting DNL.
    METHODS: Forty consecutive non-diabetic individuals with and without a history of NAFL were recruited for this observational study. After phenotyping, subjects fasted for 24-hr, and hepatic metabolism was interrogated using a combination of 2H2O and 13C tracers, magnetic resonance spectroscopy, and high-resolution mass spectrometry.
    RESULTS: Within a subset of subjects, DNL was detectable after a 24-hr fast and was more prominent in those with NAFL, though it was poorly correlated with steatosis. However, fasting DNL negatively correlated with hepatic β-oxidation and ketogenesis and positively correlated with citrate synthesis. Subjects with NAFL but undetectable fasting DNL (25th percentile) were comparatively normal. However, those with the highest fasting DNL (75th percentile) were intransigent to the effects of fasting on the concentration of insulin, NEFA, and ketones. Additionally, they sustained glycogenolysis and spared the loss of oxaloacetate to gluconeogenesis in favor of citrate synthesis, which correlated with DNL and diminished ketogenesis.
    CONCLUSION: Metabolic flux analysis in fasted subjects indicates that shared metabolic mechanisms link the dysregulations of hepatic DNL, ketogenesis, and the TCA cycle in NAFL.
    TRIAL REGISTRATION: Data obtained during the enrollment/non-intervention phase of Effect of Vitamin E on Non-Alcoholic Fatty Liver Disease; ClinicalTrials.gov NCT02690792.
    Keywords:  Endocrinology; Fatty acid oxidation; Hepatology; Intermediary metabolism
    DOI:  https://doi.org/10.1172/JCI167442
  10. Commun Biol. 2023 Mar 15. 6(1): 269
    Antimicrobial protein REG3A regulates glucose homeostasis and insulin resistance in obese diabetic mice.
    Patrick Gonzalez, Alexandre Dos Santos, Marion Darnaud, Nicolas Moniaux, Delphine Rapoud, Claire Lacoste, Tung-Son Nguyen, Valentine S Moullé, Alice Deshayes, Gilles Amouyal, Paul Amouyal, Christian Bréchot, Céline Cruciani-Guglielmacci, Fabrizio Andréelli, Christophe Magnan, Jamila Faivre.
      Innate immune mediators of pathogen clearance, including the secreted C-type lectins REG3 of the antimicrobial peptide (AMP) family, are known to be involved in the regulation of tissue repair and homeostasis. Their role in metabolic homeostasis remains unknown. Here we show that an increase in human REG3A improves glucose and lipid homeostasis in nutritional and genetic mouse models of obesity and type 2 diabetes. Mice overexpressing REG3A in the liver show improved glucose homeostasis, which is reflected in better insulin sensitivity in normal weight and obese states. Delivery of recombinant REG3A protein to leptin-deficient ob/ob mice or wild-type mice on a high-fat diet also improves glucose homeostasis. This is accompanied by reduced oxidative protein damage, increased AMPK phosphorylation and insulin-stimulated glucose uptake in skeletal muscle tissue. Oxidative damage in differentiated C2C12 myotubes is greatly attenuated by REG3A, as is the increase in gp130-mediated AMPK activation. In contrast, Akt-mediated insulin action, which is impaired by oxidative stress, is not restored by REG3A. These data highlight the importance of REG3A in controlling oxidative protein damage involved in energy and metabolic pathways during obesity and diabetes, and provide additional insight into the dual function of host-immune defense and metabolic regulation for AMP.
    DOI:  https://doi.org/10.1038/s42003-023-04616-5
  11. Food Sci Biotechnol. 2023 Mar;32(4): 577-587
    Effects of black raspberry extract on gut microbiota, microbial metabolites, and expressions of the genes involved in cholesterol and bile acid metabolisms in rats fed excessive choline with a high-fat diet.
    Taehwan Lim, Kiuk Lee, Ryun Hee Kim, Juhee Ryu, Kwang Hyun Cha, Sun Young Park, Song Yi Koo, Keum Taek Hwang.
      In our previous study, black raspberry (BR) reduced the serum levels of trimethylamine-N-oxide and cholesterol in rats fed excessive choline with a high-fat diet (HFC). We hypothesized that gut microbiota could play a crucial role in the production of trimethylamine and microbial metabolites, and BR could influence gut microbial composition. This study aimed to elucidate the role of BR on changes in gut microbiota and microbial metabolites in the rats. The phylogenetic diversity of gut microbiota was reduced in the rats fed HFC, while that in the BR-fed group was restored. The BR supplementation enriched Bifidobacterium and reduced Clostridium cluster XIVa. In the BR-fed group, most cecal bile acids and hippuric acid increased, while serum lithocholic acid was reduced. The BR supplementation upregulated Cyp7a1 and downregulated Srebf2. These results suggest that BR extract may change gut bacterial community, modulate bile acids, and regulate gene expression toward reducing cholesterol.
    Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-023-01267-4.
    Keywords:  Bile acid; CYP7A1; Choline; Gut microbiome; Rubus occidentalis; TMAO
    DOI:  https://doi.org/10.1007/s10068-023-01267-4
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