bims-liverm 2023-02-05 papers

bims-liverm

Biomed News

on Liver Metabolism

Issue of 2023–02–05
seven papers selected by

Combinatorial therapy with BAR502 and UDCA resets FXR and GPBAR1 signaling and reverses liver histopathology in a model of NASH.
Combining ASBT inhibitor and FGF15 treatments enhances therapeutic efficacy against cholangiopathy in female but not male Cyp2c70 knockout mice.
Psoralen induces liver injury and affects hepatic bile acids metabolism in female and male C57BL/6J mice.
Elevated oxysterol and N-palmitoyl-O-phosphocholineserine levels in congenital disorders of glycosylation.
Improving human mesenchymal stem cell-derived hepatic cell energy metabolism by manipulating glucose homeostasis and glucocorticoid signaling.
Metabolic changes in bile acids with pregnancy progression and their correlation with perinatal complications in intrahepatic cholestasis of pregnant patients.
Investigating bile acid-mediated cholestatic drug-induced liver injury using a mechanistic model of multidrug resistance protein 3 (MDR3) inhibition.

Sci Rep. 2023 Jan 28. 13(1): 1602

Combinatorial therapy with BAR502 and UDCA resets FXR and GPBAR1 signaling and reverses liver histopathology in a model of NASH.

Silvia Marchianò, Michele Biagioli, Elva Morretta, Cristina Di Giorgio, Rosalinda Roselli, Martina Bordoni, Rachele Bellini, Ginevra Urbani, Carmen Massa, Maria Chiara Monti, Angela Zampella, Eleonora Distrutti, Stefano Fiorucci.

Non-alcoholic steatosis (NAFLD) and steatohepatitis (NASH) are two highly prevalent human disorders for which therapy remains suboptimal. Bile acids are signaling molecules acting on two main receptors the Farnesoid-x-receptor (FXR) and G protein coupled receptor GPB AR1. Clinical trials have shown that FXR agonism might result in side effects along with lack of efficacy in restoring liver histopathology. For these reasons a multi-targets therapy combined FXR agonists with agent targeting additional molecular mechanisms might have improved efficacy over selective FXR agonists. In the present study we have compared the effects of BAR502, a dual FXR/GPBAR1 ligand) alone or in combination with ursodeoxycholic acid (UDCA) in a model of NAFLD/NASH induced by feeding mice with a Western diet for 10 weeks. The results demonstrated that while BAR502 and UDCA partially protected against liver damage caused by Western diet, the combination of the two, reversed the pro-atherogenic lipid profile and completely reversed the histopathology damage, attenuating liver steatosis, ballooning, inflammation and fibrosis. Additionally, while both agents increased insulin sensitivity and bile acid signaling, the combination of the two, modulated up top 85 genes in comparison of mice feed a Western diet, strongly reducing expression of inflammatory markers such as chemokines and cytokines. Additionally, the combination of the two agents redirected the bile acid metabolism toward bile acid species that are GPBAR1 agonist while reduced liver bile acid content and increased fecal excretion. Together, these data, highlight the potential role for a combinatorial therapy based on BAR502 and UDCA in treating of NAFLD.

DOI: https://doi.org/10.1038/s41598-023-28647-4
J Lipid Res. 2023 Feb 01. pii: S0022-2275(23)00013-5. [Epub ahead of print] 100340

Combining ASBT inhibitor and FGF15 treatments enhances therapeutic efficacy against cholangiopathy in female but not male Cyp2c70 knockout mice.

Mohammad Nazmul Hasan, Jianglei Chen, David Matye, Huaiwen Wang, Wenyi Luo, Lijie Gu, Yung Dai Clayton, Yanhong Du, Tiangang Li.

  Therapeutic reduction of hydrophobic bile acids exposure is considered beneficial in cholestasis. The Cyp2c70 KO mice lack hydrophilic muricholic acids and have a human-like hydrophobic bile acid pool resulting in hepatobiliary injury. This study investigates if combining an apical sodium-dependent bile acid transporter (ASBT) inhibitor GSK2330672 (GSK) and fibroblast growth factor-15 (FGF15) overexpression, via simultaneous inhibition of bile acid synthesis and gut bile acid uptake, achieves enhanced therapeutic efficacy in alleviating hepatobiliary injury in Cyp2c70 KO mice. The effects of GSK, AAV-FGF15, and the combined treatment on bile acid metabolism and cholangiopathy were compared in Cyp2c70 KO mice. In female Cyp2c70 KO mice with more severe cholangiopathy than male Cyp2c70 KO mice, the combined treatment was more effective in reversing portal inflammation, ductular reaction and fibrosis than AAV-FGF15, while GSK was largely ineffective. The combined treatment reduced bile acid pool by ∼80% compared to ∼50% reduction by GSK or AAV-FGF15, and enriched tauro-ursodeoxycholic acid in the bile. Interestingly, the male Cyp2c70 KO mice treated with AAV-FGF15 or GSK showed attenuated cholangiopathy and portal fibrosis, but the combined treatment was ineffective despite reducing bile acid pool. Both male and female Cyp2c70 KO mice showed impaired gut barrier integrity. AAV-FGF15 and the combined treatment, but not GSK, reduced gut exposure to lithocholic acid and improved gut barrier function. In conclusion, the combined treatment improved therapeutic efficacy against cholangiopathy than either single treatment in the female but not male Cyp2c70 KO mice by reducing bile acid pool size and hydrophobicity.

Keywords:  ASBT; Bile acid; CYP2C70; CYP7A1; FXR; cholestasis

DOI:  https://doi.org/10.1016/j.jlr.2023.100340
Phytother Res. 2023 Feb 01.

Psoralen induces liver injury and affects hepatic bile acids metabolism in female and male C57BL/6J mice.

Meng-Ying Chen, Qin Wang, Zhao-Jun Meng, Wei-Jie Men, Ju-Yang Huang, Bin Yu, Kun Zhou.

  Psoralen is a major component of Fructus Psoraleae that could induce liver injury. In this study, C57BL/6J mice were administered with psoralen at doses of 80 mg/kg for 3, 7 and 14 days. Blood and liver samples were collected for serum biochemistry and histopathology examinations, respectively. Psoralen led to liver injury with significantly increased liver weight and liver coefficient and up regulated serum ALT, AST and TG but down regulated serum TC and TP. The expression of bile acid-associated transporters and enzymes was detected by western blot, and the results showed that psoralen significantly down-regulates the expressions of CYP7A1, CYP27A1, BSEP and OSTα protein while up-regulates the expressions of HMGCR and FASN, resulting in the obstacles of bile acid efflux in the liver. The contents of 24 kinds of bile acids in the liver were measured by LC-MS/MS, and the results showed that psoralen led to the accumulation of unconjugated bile acids in the liver, such as ALCA and CA, which were more severe in male mice than female mice. It was indicated that psoralen may disrupt the balance of bile acid metabolism by inhibiting the expression of the efflux transporter, which then leads to liver damage.

Keywords:  bile acid; hepatotoxicity; psoralen; synthetase; transporter

DOI:  https://doi.org/10.1002/ptr.7739
J Inherit Metab Dis. 2023 Jan 31.

Elevated oxysterol and N-palmitoyl-O-phosphocholineserine levels in congenital disorders of glycosylation.

An N Dang Do, Irene J Chang, Xutian Jiang, Lynne A Wolfe, Bobby G Ng, Christina Lam, Rhonda E Schnur, Katrina Allis, Hana Hansikova, Nina Ondruskova, Shawn D O'Connor, Amarilis Sanchez-Valle, Arve Vollo, Raymond Y Wang, Zoe Wolfenson, John Perreault, Daniel S Ory, Hudson H Freeze, J Lawrence Merritt, Forbes D Porter.

  Congenital disorders of glycosylation (CDG) and Niemann-Pick type C (NPC) disease are inborn errors of metabolism that can both present with infantile-onset severe liver disease and other multisystemic manifestations. Plasma bile acid and N-palmitoyl-O-phosphocholineserine (PPCS) are screening biomarkers with proposed improved sensitivity and specificity for NPC. We report an infant with ATP6AP1-CDG who presented with cholestatic liver failure and elevated plasma oxysterols and bile acid, mimicking NPC clinically and biochemically. On further investigation, PPCS, but not the bile acid derivative N-(3β,5α,6β-trihydroxy-cholan-24-oyl) glycine (TCG), were elevated in plasma samples from individuals with ATP6AP1-, ALG1-, ALG8-, and PMM2-CDG. These findings highlight the importance of keeping CDG within the diagnostic differential when evaluating children with early onset severe liver disease and elevated bile acid or PPCS to prevent delayed diagnosis and treatment.

Keywords:  ATP6AP1; N-palmitoyl-O-phosphocholineserine (PPCS); Niemann-pick type C (NPC); bile acids; congenital disorders of glycosylation (CDG); oxysterols

DOI:  https://doi.org/10.1002/jimd.12595
Front Endocrinol (Lausanne). 2022 ;13 1043543

Improving human mesenchymal stem cell-derived hepatic cell energy metabolism by manipulating glucose homeostasis and glucocorticoid signaling.

Joana Saraiva Rodrigues, Andreia Faria-Pereira, Sérgio Póvoas Camões, Ana Sofia Serras, Vanessa Alexandra Morais, Jorge Lira Ruas, Joana Paiva Miranda.

   Introduction: The development of reliable hepatic in vitro models may provide insights into disease mechanisms, linking hepatocyte dysmetabolism and related pathologies. However, several of the existing models depend on using high concentrations of hepatocyte differentiation-promoting compounds, namely glucose, insulin, and dexamethasone, which is among the reasons that have hampered their use for modeling metabolism-related diseases. This work focused on modulating glucose homeostasis and glucocorticoid concentration to improve the suitability of a mesenchymal stem-cell (MSC)-derived hepatocyte-like cell (HLC) human model for studying hepatic insulin action and disease modeling.
Methods: We have investigated the role of insulin, glucose and dexamethasone on mitochondrial function, insulin signaling and carbohydrate metabolism, namely AKT phosphorylation, glycogen storage ability, glycolysis and gluconeogenesis, as well as fatty acid oxidation and bile acid metabolism gene expression in HLCs. In addition, we evaluated cell morphological features, albumin and urea production, the presence of hepatic-specific markers, biotransformation ability and mitochondrial function.
Results: Using glucose, insulin and dexamethasone levels close to physiological concentrations improved insulin responsiveness in HLCs, as demonstrated by AKT phosphorylation, upregulation of glycolysis and downregulation of Irs2 and gluconeogenesis and fatty acid oxidation pathways. Ammonia detoxification, EROD and UGT activities and sensitivity to paracetamol cytotoxicity were also enhanced under more physiologically relevant conditions.
Conclusion: HLCs kept under reduced concentrations of glucose, insulin and dexamethasone presented an improved hepatic phenotype and insulin sensitivity demonstrating superior potential as an in vitro platform for modeling energy metabolism-related disorders, namely for the investigation of the insulin signaling pathway.

Keywords:  alternative hepatic in vitro models; dexamethasone; glucose; hepatocyte-like cells; insulin; mesenchymal stem cells; metabolism

DOI:  https://doi.org/10.3389/fendo.2022.1043543
Sci Rep. 2023 Jan 28. 13(1): 1608

Metabolic changes in bile acids with pregnancy progression and their correlation with perinatal complications in intrahepatic cholestasis of pregnant patients.

Zhixin Ma, Yifeng Liu, Lin Chai, Guochen Jin, Yanni Sun, Shaomin Zhou, Peiyuan Yin, Siwen Wang, Yuning Zhu, Dan Zhang, Shiming Lu, Bo Zhu.

Intrahepatic cholestasis of pregnancy (ICP) is a rare liver disease occurring during pregnancy that is characterized by disordered bile acid (BA) metabolism. It is related to adverse clinical outcomes in both the mother and fetus. Our aim was to evaluate the BA metabolism profiles in different types of ICP and investigate the association between specific BAs and perinatal complications in ICP patients. We consecutively evaluated 95 patients with ICP, in which 53 patients were diagnosed with early-onset ICP (EICP) and 42 patients were diagnosed with late-onset ICP (LICP). Concentrations of 15 BA components were detected using high-performance liquid chromatography tandem mass spectrometry. Clinical information was abstracted from the medical records. The percentage of conjugated bile acids increased in ICP patients. Specifically, taurocholic acid (TCA) accumulated in LICP patients, and glycocholic acid (GCA) predominated in EICP patients. A higher preterm birth incidence was observed among ICP patients. Albumin, total bile acids, total bilirubin and GCA percentage values at ICP diagnosis predicts 83.5% of preterm birth in EICP, and the percentage of TCA in total bile acids at ICP diagnosis predicts 93.2% of preterm birth in LICP. This analysis showed that the BA metabolism profiles of EICP and LICP were distinct. Increased hepatic load was positively correlated with preterm birth in EICP. An elevated TCA percentage in total bile acids provides a biomarker to predict preterm birth in LICP.

DOI: https://doi.org/10.1038/s41598-022-22974-8
Front Pharmacol. 2022 ;13 1085621

Investigating bile acid-mediated cholestatic drug-induced liver injury using a mechanistic model of multidrug resistance protein 3 (MDR3) inhibition.

James J Beaudoin, Kyunghee Yang, Jeffry Adiwidjaja, Guncha Taneja, Paul B Watkins, Scott Q Siler, Brett A Howell, Jeffrey L Woodhead.

  Inhibition of the canalicular phospholipid floppase multidrug resistance protein 3 (MDR3) has been implicated in cholestatic drug-induced liver injury (DILI), which is clinically characterized by disrupted bile flow and damage to the biliary epithelium. Reduction in phospholipid excretion, as a consequence of MDR3 inhibition, decreases the formation of mixed micelles consisting of bile acids and phospholipids in the bile duct, resulting in a surplus of free bile acids that can damage the bile duct epithelial cells, i.e., cholangiocytes. Cholangiocytes may compensate for biliary increases in bile acid monomers via the cholehepatic shunt pathway or bicarbonate secretion, thereby influencing viability or progression to toxicity. To address the unmet need to predict drug-induced bile duct injury in humans, DILIsym, a quantitative systems toxicology model of DILI, was extended by representing key features of the bile duct, cholangiocyte functionality, bile acid and phospholipid disposition, and cholestatic hepatotoxicity. A virtual, healthy representative subject and population (n = 285) were calibrated and validated utilizing a variety of clinical data. Sensitivity analyses were performed for 1) the cholehepatic shunt pathway, 2) biliary bicarbonate concentrations and 3) modes of MDR3 inhibition. Simulations showed that an increase in shunting may decrease the biliary bile acid burden, but raise the hepatocellular concentrations of bile acids. Elevating the biliary concentration of bicarbonate may decrease bile acid shunting, but increase bile flow rate. In contrast to competitive inhibition, simulations demonstrated that non-competitive and mixed inhibition of MDR3 had a profound impact on phospholipid efflux, elevations in the biliary bile acid-to-phospholipid ratio, cholangiocyte toxicity, and adaptation pathways. The model with its extended bile acid homeostasis representation was furthermore able to predict DILI liability for compounds with previously studied interactions with bile acid transport. The cholestatic liver injury submodel in DILIsym accounts for several processes pertinent to bile duct viability and toxicity and hence, is useful for predictions of MDR3 inhibition-mediated cholestatic DILI in humans.

Keywords:  DILI (drug-induced liver injury); bile duct; computational biology; drug development; drug discovery; quantitative systems toxicology modeling

DOI:  https://doi.org/10.3389/fphar.2022.1085621