bims-liverm 2023-04-16 papers

Issue of 2023–04–16
five papers selected by

Hepatol Commun. 2023 May 01. pii: e0109. [Epub ahead of print]7(5):

Elevated bile acids are associated with left ventricular structural changes in biliary atresia.

Manpreet K Virk, Muhammad Umair M Mian, Dalia A Bashir, John K Wilkes, Tobias Schlingman, Saul Flores, Curtis Kennedy, Fong Lam, Ayse A Arikan, Trung Nguyen, Krupa Mysore, Nhu Thao Nguyen Galvan, Jorge Coss-Bu, Saul J Karpen, Sanjiv Harpavat, Moreshwar S Desai.

BACKGROUND: In children with biliary atresia (BA), pathologic structural changes within the heart, which define cirrhotic cardiomyopathy, are associated with adverse perioperative outcomes. Despite their clinical relevance, little is known about the pathogenesis and triggers of pathologic remodeling. Bile acid excess causes cardiomyopathy in experimental cirrhosis, but its role in BA is poorly understood.
METHODS: Echocardiographic parameters of left ventricular (LV) geometry [LV mass (LVM), LVM indexed to height, left atrial volume indexed to BSA (LAVI), and LV internal diameter (LVID)] were correlated with circulating serum bile acid concentrations in 40 children (52% female) with BA listed for transplantation. A receiver-operating characteristic curve was generated to determine optimal threshold values of bile acids to detect pathologic changes in LV geometry using Youden index. Paraffin-embedded human heart tissue was separately analyzed by immunohistochemistry for the presence of bile acid-sensing Takeda G-protein-coupled membrane receptor type 5.
RESULTS: In the cohort, 52% (21/40) of children had abnormal LV geometry; the optimal bile acid concentration to detect this abnormality with 70% sensitivity and 64% specificity was 152 µmol/L (C-statistics=0.68). Children with bile acid concentrations >152 µmol/L had ∼8-fold increased odds of detecting abnormalities in LVM, LVM index, left atrial volume index, and LV internal diameter. Serum bile acids positively correlated with LVM, LVM index, and LV internal diameter. Separately, Takeda G-protein-coupled membrane receptor type 5 protein was detected in myocardial vasculature and cardiomyocytes on immunohistochemistry.
CONCLUSION: This association highlights the unique role of bile acids as one of the targetable potential triggers for myocardial structural changes in BA.

DOI: https://doi.org/10.1097/HC9.0000000000000109

J Nutr Biochem. 2023 Apr 07. pii: S0955-2863(23)00080-3. [Epub ahead of print] 109347

Dietary cholesterol drives the development of non-alcoholic steatohepatitis by altering gut microbiota mediated bile acid metabolism in high-fat diet fed mice.

Xuebin Gao, Xiaozhuan Lin, Yan Xin, Xuan Zhu, Xiang Li, Ming Chen, Zhigang Huang, Honghui Guo.

Non-alcoholic fatty liver disease (NAFLD) is the most widespread chronic liver disorder globally. Unraveling the pathogenesis of simple fatty liver to non-alcoholic steatohepatitis (NASH) has important clinical significance for improving the prognosis of NAFLD. Here, we explored the role of a high-fat diet alone or combined with high cholesterol in causing NASH progression. Our results demonstrated that high dietary cholesterol intakes accelerate the progression of spontaneous NAFLD and induces liver inflammation in mice. An elevation of hydrophobic unconjugated bile acids cholic acid (CA), deoxycholic acid (DCA), muricholic acid and chenodeoxycholic acid, was observed in high-fat and high-cholesterol diet fed mice. Full-length sequencing of the 16S rRNA gene of gut microbiota revealed a significant increase in the abundance of Bacteroides, Clostridium and Lactobacillus that possess bile salt hydrolase activity. Furthermore, the relative abundance of these bacterial species was positively correlated with content of unconjugated bile acids in liver. Moreover, the expression of genes related to bile acid reabsorption (organic anion-transporting polypeptides, Na+-taurocholic acid cotransporting polypeptide, apical sodium dependent bile acid transporter and organic solute transporter β) was found to be increased in mice with a high-cholesterol diet. Lastly, we observed that hydrophobic bile acids CA and DCA induce an inflammatory response in free fatty acids-induced steatotic HepG2 cells. In conclusion, high dietary cholesterol promotes the development of NASH by altering gut microbiota composition and abundance and thereby influencing with bile acid metabolism.

Keywords: Non-alcoholic steatohepatitis; bile acid; dietary cholesterol; gut microbiota

DOI: https://doi.org/10.1016/j.jnutbio.2023.109347

Front Endocrinol (Lausanne). 2023 ;14 1153205

The association between total bile acid and bone mineral density among patients with type 2 diabetes.

Song Yang, Hongyun Li, Yuanyuan Gu, Qiang Wang, Li Dong, Chao Xu, Yuxin Fan, Ming Liu, Qingbo Guan, Lixing Ma.

Objective: Bile acids have underlying protective effects on bones structure. Long-term diabetes also causes skeletal disorders including osteoporosis, Charcot arthropathy and renal osteodystrophy. Nevertheless, few studies have reported whether bile acid is associated with bone metabolism in diabetics. This study aimed to explore the relationship between total bile acid (TBA) and bone mineral density (BMD) among patients with type 2 diabetes mellitus (T2DM).
Methods: We retrospectively included 1,701 T2DM patients who were hospitalized in Taian City Central Hospital (TCCH), Shandong Province, China between January 2017 to December 2019. The participants were classified into the osteopenia (n = 573), osteoporosis (n= 331) and control groups (n= 797) according to BMD in the lumbar spine and femoral. The clinical parameters, including TBA, bilirubin, vitamin D, calcium, phosphorus and alkaline phosphatase were compared between groups. Multiple linear regression was used to analyze the relationship between TBA and BMD in lumbar spine, femoral, trochiter, ward's triangle region. A logistic regression was conducted to develop a TBA-based diagnostic model for differentiating abnormal bone metabolism from those with normal BMD. We evaluated the performance of model using ROC curves.
Results: The TBA level was significantly higher in patients with osteoporosis (Median[M]= 3.300 μmol/L, interquartile range [IQR] = 1.725 to 5.250 μmol/L) compared to the osteopenia group (M = 3.200 μmol/L, IQR = 2.100 to 5.400 μmol/L) and control group (M = 2.750 μmol/L, IQR = 1.800 to 4.600 μmol/L) (P <0.05). Overall and subgroup analyses indicated that TBA was negatively associated with BMD after adjusted for the co-variates (i.e., age, gender, diabetes duration, BMI, total bilirubin, direct bilirubin, indirect bilirubin) (P <0.05). Logistic regression revealed that higher TBA level was associated with increased risk for abnormal bone metabolism (OR = 1.044, 95% CI = 1.005 to 1.083). A TBA-based diagnostic model was established to identify individuals with abnormal bone metabolism (T-score ≤ -1.0). The area under ROC curve (AUC) of 0.767 (95% CI = 0.730 to 0.804).
Conclusion: Our findings demonstrated the potential role of bile acids in bone metabolism among T2DM patients. The circulating TBA might be employed as an indicator of abnormal bone metabolism.

Keywords: abnormal bone metabolism; bone mineral density (BMD); osteoporosis; total bile acid (TBA); type 2 diabetes mellitus (T2DM)

DOI: https://doi.org/10.3389/fendo.2023.1153205

Hepatol Commun. 2023 May 01. pii: e0127. [Epub ahead of print]7(5):

FXR and NASH: an avenue for tissue-specific regulation.

Zakiyah Henry, Vik Meadows, Grace L Guo.

NASH is within the spectrum of NAFLD, a liver condition encompassing liver steatosis, inflammation, hepatocyte injury, and fibrosis. The prevalence of NASH-induced cirrhosis is rapidly rising and has become the leading indicator for liver transplantation in the US. There is no Food and Drug Administration (FDA)-approved pharmacological intervention for NASH. The farnesoid X receptor (FXR) is essential in regulating bile acid homeostasis, and dysregulation of bile acids has been implicated in the pathogenesis of NASH. As a result, modulators of FXR that show desirable effects in mitigating key characteristics of NASH have been developed as promising therapeutic approaches. However, global FXR activation causes adverse effects such as cholesterol homeostasis imbalance and pruritus. The development of targeted FXR modulation is necessary for ideal NASH therapeutics, but information regarding tissue-specific and cell-specific FXR functionality is limited. In this review, we highlight FXR activation in the regulation of bile acid homeostasis and NASH development, examine the current literature on tissue-specific regulation of nuclear receptors, and speculate on how FXR regulation will be beneficial in the treatment of NASH.

DOI: https://doi.org/10.1097/HC9.0000000000000127

Front Pharmacol. 2023 ;14 1147495

Effect of mTOR inhibitors on sodium taurocholate cotransporting polypeptide (NTCP) function in vitro.

Chitra Saran, Henry Ho, Paavo Honkakoski, Kim L R Brouwer.

The sodium taurocholate cotransporting polypeptide (NTCP; gene name SLC10A1) is the primary hepatic basolateral uptake transporter for conjugated bile acids and the entry receptor for the hepatitis B and D virus (HBV/HDV). Regulation of human NTCP remains a knowledge gap due to significant species differences in substrate and inhibitor selectivity and plasma membrane expression. In the present study, various kinase inhibitors were screened for inhibition of NTCP function and taurocholate (TCA) uptake using NTCP-transfected HuH-7 cells. This study identified everolimus, an mTOR inhibitor and macrocyclic immunosuppressive drug, as an NTCP inhibitor with modest potency (IC50 = 6.7-8.0 µM). Further investigation in differentiated HuH-7 cells expressing NTCP and NTCP-overexpressing Flp-In T-REx 293 cells revealed that the mechanism of action of everolimus on NTCP is direct inhibition and mTOR-independent. Structural analogs of everolimus inhibited NTCP-mediated TCA uptake, however, functional analogs did not affect NTCP-mediated TCA transport, providing further evidence for direct inhibition. This work contributes to the growing body of literature suggesting that NTCP-mediated bile acid uptake may be inhibited by macrocyclic peptides, which may be further exploited to develop novel medications against HBV/HDV.

Keywords: Flp-In T-REx 293 cells; HuH-7 cells; NTCP; everolimus; hepatitis virus; kinase inhibitors; mTOR inhibitors; taurocholate

DOI: https://doi.org/10.3389/fphar.2023.1147495