bims-liverm Biomed News
on Liver Metabolism
Issue of 2023‒04‒02
seven papers selected by
Marti Cadena Sandoval
Columbia University
  1. The Pathological Effects of Circulating Hydrophobic Bile Acids in Alzheimer's Disease.
  2. Bile acids as metabolic regulators: an update.
  3. Glycoursodeoxycholic acid regulates bile acids level and alters gut microbiota and glycolipid metabolism to attenuate diabetes.
  4. Discovery of BAR502, as potent steroidal antagonist of leukemia inhibitory factor receptor for the treatment of pancreatic adenocarcinoma.
  5. Native liver survival in bile salt export pump deficiency: results of a retrospective cohort study.
  6. Effects of Atorvastatin on Bile Acid Metabolism in High-Fat Diet-Fed ApoE-/- Mice.
  7. Elevated Bile Acid Is Associated with Worsened Impaired Glucose Homeostasis in Pancreatic Ductal Adenocarcinoma Patients with Extrahepatic Cholestasis through Increased Hepatic Insulin Clearance.
  1. J Alzheimers Dis Rep. 2023 ;7(1): 173-211
    The Pathological Effects of Circulating Hydrophobic Bile Acids in Alzheimer's Disease.
    Touraj Ehtezazi, Khalid Rahman, Rhys Davies, Andrew G Leach.
      Recent clinical studies have revealed that the serum levels of toxic hydrophobic bile acids (deoxy cholic acid, lithocholic acid [LCA], and glycoursodeoxycholic acid) are significantly higher in patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI) when compared to control subjects. The elevated serum bile acids may be the result of hepatic peroxisomal dysfunction. Circulating hydrophobic bile acids are able to disrupt the blood-brain barrier and promote the formation of amyloid-β plaques through enhancing the oxidation of docosahexaenoic acid. Hydrophobic bile acid may find their ways into the neurons via the apical sodium-dependent bile acid transporter. It has been shown that hydrophobic bile acids impose their pathological effects by activating farnesoid X receptor and suppressing bile acid synthesis in the brain, blocking NMDA receptors, lowering brain oxysterol levels, and interfering with 17β-estradiol actions such as LCA by binding to E2 receptors (molecular modelling data exclusive to this paper). Hydrophobic bile acids may interfere with the sonic hedgehog signaling through alteration of cell membrane rafts and reducing brain 24(S)-hydroxycholesterol. This article will 1) analyze the pathological roles of circulating hydrophobic bile acids in the brain, 2) propose therapeutic approaches, and 3) conclude that consideration be given to reducing/monitoring toxic bile acid levels in patients with AD or aMCI, prior/in combination with other treatments.
    Keywords:  Alzheimer’s disease; blocking NMDA receptors; blood-brain barrier; declining cognitive function; liver dysfunction; serum bile acids
    DOI:  https://doi.org/10.3233/ADR-220071
  2. Curr Opin Gastroenterol. 2023 Mar 10.
    Bile acids as metabolic regulators: an update.
    Tiangang Li, John Y L Chiang.
      PURPOSE OF REVIEW: This review aims to provide a concise update on recent advances in understanding of the bile acid metabolism and signaling in health and diseases.RECENT FINDINGS: CYP2C70 has been identified as the murine cytochrome p450 enzyme that mediates the synthesis of muricholic acids to account for the major different bile acid composition between human and mice. Several studies have linked nutrient sensing bile acid signaling to the regulation of hepatic autophagy-lysosome activity, an integral pathway of the cellular adaptive response to starvation. Distinct bile acid-mediated signaling mechanisms have been shown to contribute to the complex metabolic changes post bariatric surgery, suggesting that pharmacological manipulation of the enterohepatic bile acid signaling could be a potential nonsurgical alternative to weight loss surgery.
    SUMMARY: Basic and clinical studies have continued to discover novel roles of the enterohepatic bile acid signaling in regulation of key metabolic pathways. Such knowledge forms the molecular basis needed for developing safe and effective bile acid-based therapeutics for treating metabolic and inflammatory diseases.
    DOI:  https://doi.org/10.1097/MOG.0000000000000934
  3. Gut Microbes. 2023 Jan-Dec;15(1):15(1): 2192155
    Glycoursodeoxycholic acid regulates bile acids level and alters gut microbiota and glycolipid metabolism to attenuate diabetes.
    Bingting Chen, Yu Bai, Fenglian Tong, Junlin Yan, Rui Zhang, Yewei Zhong, Huiwen Tan, Xiaoli Ma.
      Accumulating evidence suggests that the bile acid regulates type 2 diabetes mellitus (T2DM) through gut microbiota-host interactions. However, the mechanisms underlying such interactions have been unclear. Here, we found that glycoursodeoxycholic acid (GUDCA) positively regulates gut microbiota by altering bile acid metabolism. GUDCA in mice resulted in higher taurolithocholic acid (TLCA) level and Bacteroides vulgatus abundance. Together, these changes resulted in the activation of the adipose G-protein-coupled bile acid receptor, GPBAR1 (TGR5) and upregulated expression of uncoupling protein UCP-1, resulting in elevation of white adipose tissue thermogenesis. The anti-T2DM effects of GUDCA are linked with the regulation of the bile acid and gut microbiota composition. This study suggests that altering bile acid metabolism, modifying the gut microbiota may be of value for the treatment of T2DM.
    Keywords:  Type 2 diabetes; bile acids; glycoursodeoxycholic acid; gut microbiota
    DOI:  https://doi.org/10.1080/19490976.2023.2192155
  4. Front Oncol. 2023 ;13 1140730
    Discovery of BAR502, as potent steroidal antagonist of leukemia inhibitory factor receptor for the treatment of pancreatic adenocarcinoma.
    Cristina Di Giorgio, Rachele Bellini, Antonio Lupia, Carmen Massa, Martina Bordoni, Silvia Marchianò, Rosalinda Rosselli, Valentina Sepe, Pasquale Rapacciuolo, Federica Moraca, Elva Morretta, Patrizia Ricci, Ginevra Urbani, Maria Chiara Monti, Michele Biagioli, Eleonora Distrutti, Bruno Catalanotti, Angela Zampella, Stefano Fiorucci.
      Introduction: The leukemia inhibitory factor (LIF), is a cytokine belonging to IL-6 family, whose overexpression correlate with poor prognosis in cancer patients, including pancreatic ductal adenocarcinoma (PDAC). LIF signaling is mediate by its binding to the heterodimeric LIF receptor (LIFR) complex formed by the LIFR receptor and Gp130, leading to JAK1/STAT3 activation. Bile acids are steroid that modulates the expression/activity of membrane and nuclear receptors, including the Farnesoid-X-Receptor (FXR) and G Protein Bile Acid Activated Receptor (GPBAR1).Methods: Herein we have investigated whether ligands to FXR and GPBAR1 modulate LIF/LIFR pathway in PDAC cells and whether these receptors are expressed in human neoplastic tissues.
    Results: The transcriptome analysis of a cohort of PDCA patients revealed that expression of LIF and LIFR is increased in the neoplastic tissue in comparison to paired non-neoplastic tissues. By in vitro assay we found that both primary and secondary bile acids exert a weak antagonistic effect on LIF/LIFR signaling. In contrast, BAR502 a non-bile acid steroidal dual FXR and GPBAR1 ligand, potently inhibits binding of LIF to LIFR with an IC50 of 3.8 µM.
    Discussion: BAR502 reverses the pattern LIF-induced in a FXR and GPBAR1 independent manner, suggesting a potential role for BAR502 in the treatment of LIFR overexpressing-PDAC.
    Keywords:  EMT; LIF; LIFR; PDAC; bile acids; proliferation; steroid
    DOI:  https://doi.org/10.3389/fonc.2023.1140730
  5. Hepatol Commun. 2023 Apr 01. pii: e0092. [Epub ahead of print]7(4):
    Native liver survival in bile salt export pump deficiency: results of a retrospective cohort study.
    Eva-Doreen Pfister, Veronika K Jaeger, André Karch, Denys Shay, Nagoud Schukfeh, Johanna Ohlendorf, Norman Junge, Imeke Goldschmidt, Amelie Stalke, Verena Keitel-Anselmino, Ulrich Baumann.
      BACKGROUND: Bile salt export pump (ABCB11) deficiency [Progressive familial intrahepatic cholestasis (PFIC2)] is the most common genetic cause of PFIC and is associated with pruritus and progressive liver disease. Surgical biliary diversion or pharmacological [ileal bile acid transporter inhibitor (IBATi)] approaches can be used to block the recirculation of bile acids to the liver. There is a paucity of detailed data on the natural history and, in particular, the longitudinal evolution of bile acid levels to predict treatment response. Cross-sectional data from large international consortia suggested a maximum cutoff value of bile acids after the intervention to predict a successful outcome.METHODS: This retrospective, single-center, cohort study included all patients with confirmed biallelic pathogenic ABCB11 genotype PFIC2 treated at our institution with ≥2 years follow-up. The outcomes of interventions and predictors of long-term health were analyzed.
    RESULTS: Forty-eight cases were identified with PFIC2. Eighteen received partial external biliary diversion (PEBD) surgery, and 22 patients underwent liver transplantation. Two patients developed HCC and 2 died. Improved survival with native liver was closely associated with genotype, complete normalization of serum bile acids following PEBD, and alleviation of pruritus. Persistence of mild-to-moderate elevation of bile acids or a secondary rise following normalization was associated with liver disease progression and led to transplantation, suggesting that any prolonged elevation of bile acids worsens the chance of native liver survival. Higher-grade fibrosis at the time of PEBD was not associated with reduced long-term native liver survival. Patients with PFIC2 benefit from PEBD even at a stage of advanced fibrosis.
    CONCLUSION: Serum bile acid levels are an early predictor of treatment response and might serve as the gold standard in the evaluation of novel therapies including IBATi.
    DOI:  https://doi.org/10.1097/HC9.0000000000000092
  6. J Cardiovasc Pharmacol. 2023 Mar 30.
    Effects of Atorvastatin on Bile Acid Metabolism in High-Fat Diet-Fed ApoE-/- Mice.
    Wei Li, Honglin Liu, Jiyi Liang, Tao Wang, Jia Liu, Xiaofeng Pi, Wenjun Zou, Liping Qu.
      ABSTRACT: Statins are considered as the cornerstone of the prevention and treatment of atherosclerotic cardiovascular disease, where pleiotropic effects are thought to contribute greatly in addition to the lipid-lowering effect. Bile acid metabolism has been gradually reported to be involved in the antihyperlipidemic and antiatherosclerotic effects of statins, but with inconsistent results and few studies carried out on animal models of atherosclerosis. The study aimed to examine the possible role of bile acid metabolism in the lipid-lowering and antiatherosclerotic effects of atorvastatin (ATO) in high-fat diet-fed ApoE-/- mice. The results showed that the levels of liver and faecal TC as well as ileal and faecal TBA were significantly increased in mice of the model group after 20 weeks of high-fat diet feeding compared to the control group, with significantly downregulated mRNA expression of liver LXR-α, CYP7A1, BSEP and NTCP. ATO treatment further increased the levels of ileal and faecal TBA and faecal TC, but no obvious effect was observed on serum and liver TBA. In addition, ATO significantly reversed the mRNA levels of liver CYP7A1 and NTCP and no obvious changes was observed in the expression of LXR-α and BSEP. Our study suggested that statins may enhance synthesis of bile acids and facilitate the reabsorption of bile acids from the ileum via portal into the liver, possibly through the upregulation of the expression of CYP7A1 and NTCP. The results are helpful in enriching the theoretical basis for the clinical use of statins and have good translational value.
    DOI:  https://doi.org/10.1097/FJC.0000000000001425
  7. J Clin Med. 2023 Mar 17. pii: 2352. [Epub ahead of print]12(6):
    Elevated Bile Acid Is Associated with Worsened Impaired Glucose Homeostasis in Pancreatic Ductal Adenocarcinoma Patients with Extrahepatic Cholestasis through Increased Hepatic Insulin Clearance.
    Jie Yang, Chunlu Tan, Zhenjiang Zheng, Xing Wang, Xubao Liu, Yonghua Chen.
      BACKGROUND: Patients after pancreaticoduodenectomy (PD) showed improved glucose tolerance. Evidence for the effect of extrahepatic cholestasis on impaired glucose homeostasis secondary to ductal adenocarcinoma of the pancreatic head is limited.METHODS: In this prospective cross-sectional study, 50 patients with ductal adenocarcinoma of the pancreatic head were included to assess the effect of extrahepatic cholestasis on glucose tolerance status based on the oral glucose tolerance test (OGTT) before pancreatic surgery.
    RESULTS: Patients with extrahepatic cholestasis more frequently suffered from worsened impaired glucose homeostasis (prediabetes and new-onset diabetes, 95.2% vs. 58.6%, p = 0.004). Elevated bile acid level was recognized as an independent risk factor for impaired glucose homeostasis (p = 0.024, OR = 6.85). Hepatic insulin clearance (HIC) was significantly higher in patients with elevated bile acid levels (p = 0.001). A strong positive correlation was found between bile acid levels and HIC (r = 0.45, p = 0.001).
    CONCLUSIONS: This study suggested a connection between elevated bile acid levels and worsened impaired glucose homeostasis through increased insulin clearance function in ductal adenocarcinoma of pancreatic head patients.
    Keywords:  bile acid; extrahepatic cholestasis; hepatic insulin clearance; impaired glucose homeostasis; pancreatic ductal adenocarcinoma; pancreaticoduodenectomy
    DOI:  https://doi.org/10.3390/jcm12062352
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