bile acid
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Animals ◽  
2022 ◽  
Vol 12 (2) ◽  
pp. 205
Author(s):  
Di Wu ◽  
Mingjuan Gu ◽  
Zhuying Wei ◽  
Chunling Bai ◽  
Guanghua Su ◽  
...  

Myostatin (MSTN) is a major negative regulator of skeletal muscle mass and causes a variety of metabolic changes. However, the effect of MSTN knockout on bile acid metabolism has rarely been reported. In this study, the physiological and biochemical alterations of serum in MSTN+/− and wild type (WT) cattle were investigated. There were no significant changes in liver and kidney biochemical indexes. However, compared with the WT cattle, lactate dehydrogenase, total bile acid (TBA), cholesterol, and high-density lipoprotein (HDL) in the MSTN+/− cattle were significantly increased, and glucose, low-density lipoprotein (LDL), and triglycerides (TG) were significantly decreased, indicating that MSTN knockout affected glucose and lipid metabolism and total bile acids content. Targeted metabolomic analysis of the bile acids and their derivatives was performed on serum samples and found that bile acids were significantly increased in the MSTN+/− cattle compared with the WT cattle. As the only bile acid synthesis organ in the body, we performed metabolomic analysis on the liver to study the effect of MSTN knockout on hepatic metabolism. Metabolic pathway enrichment analysis of differential metabolites showed significant enrichment of the primary bile acid biosynthesis and bile secretion pathway in the MSTN+/− cattle. Targeted metabolomics data further showed that MSTN knockout significantly increased bile acid content in the liver, which may have resulted from enhanced bile acid synthesis due to the expression of bile acid synthesis genes, cholesterol 7 alpha-hydroxylase (CYP7A1) and sterol 27-hydroxylase (CYP27A1), and upregulation in the liver of the MSTN+/− cattle. These results indicate that MSTN knockout does not adversely affect bovine fitness but regulates bile acid metabolism via enhanced bile acid synthesis. This further suggests a role of MSTN in regulating metabolism.


Author(s):  
Meng-Yuan Zhang ◽  
Lingpeng Zhu ◽  
Xinhua Zheng ◽  
Tian-Hua Xie ◽  
Wenjuan Wang ◽  
...  

Background: Diabetic retinopathy (DR) is one of the most important microvascular diseases of diabetes. Our previous research demonstrated that bile acid G-protein-coupled membrane receptor (TGR5), a novel cell membrane receptor of bile acid, ameliorates the vascular endothelial cell dysfunction in DR. However, the precise mechanism leading to this alteration remains unknown. Thus, the mechanism of TGR5 in the progress of DR should be urgently explored.Methods: In this study, we established high glucose (HG)-induced human retinal vascular endothelial cells (RMECs) and streptozotocin-induced DR rat in vitro and in vivo. The expression of TGR5 was interfered through the specific agonist or siRNA to study the effect of TGR5 on the function of endothelial cell in vitro. Western blot, immunofluorescence and fluorescent probes were used to explore how TGR5 regulated mitochondrial homeostasis and related molecular mechanism. The adeno-associated virus serotype 8-shTGR5 (AAV8-shTGR5) was performed to evaluate retinal dysfunction in vivo and further confirm the role of TGR5 in DR by HE staining, TUNEL staining, PAS staining and Evans Blue dye.Results: We found that TGR5 activation alleviated HG-induced endothelial cell apoptosis by improving mitochondrial homeostasis. Additionally, TGR5 signaling reduced mitochondrial fission by suppressing the Ca2+-PKCδ/Drp1 signaling and enhanced mitophagy through the upregulation of the PINK1/Parkin signaling pathway. Furthermore, our result indicated that Drp1 inhibited mitophagy by facilitating the hexokinase (HK) 2 separation from the mitochondria and HK2-PINK1/Parkin signaling. In vivo, intraretinal microvascular abnormalities, including retinal vascular leakage, acellular capillaries and apoptosis, were poor in AAV8-shTGR5-treated group under DR, but this effect was reversed by pretreatment with the mitochondrial fission inhibitor Mdivi-1 or autophagy agonist Rapamycin.Conclusion: Overall, our findings indicated that TGR5 inhibited mitochondrial fission and enhanced mitophagy in RMECs by regulating the PKCδ/Drp1-HK2 signaling pathway. These results revealed the molecular mechanisms underlying the protective effects of TGR5 and suggested that activation of TGR5 might be a potential therapeutic strategy for DR.


2022 ◽  
Vol 12 ◽  
Author(s):  
Fangling Zhang ◽  
Xiaolin Xiao ◽  
Yong Li ◽  
Hefei Wu ◽  
Xinyu Deng ◽  
...  

GPBAR1, a transmembrane G protein-coupled receptor for bile acids, is widely expressed in multiple tissues in humans and rodents. In recent years, GPBAR1 has been thought to play an important role in bile homeostasis, metabolism and inflammation. This review specifically focuses on the function of GPBAR1 in cholestatic liver disease and summarizes the various pathways through which GPBAR1 acts in cholestatic models. GPBAR1 mainly regulates cholestasis in a holistic system of liver-gallbladder-gut formation. In the state of cholestasis, the activation of GPBAR1 could regulate liver inflammation, induce cholangiocyte regeneration to maintain the integrity of the biliary tree, control the hydrophobicity of the bile acid pool and promote the secretion of bile HCO3−. All these functions of GPBAR1 might be clear ways to protect against cholestatic diseases and liver injury. However, the characteristic of GPBAR1-mediated proliferation increases the risk of proliferation of cholangiocarcinoma in malignant transformed cholangiocytes. This dichotomous function of GPBAR1 limits its use in cholestasis. During disease treatment, simultaneous activation of GPBAR1 and FXR receptors often results in improved outcomes, and this strategy may become a crucial direction in the development of bile acid-activated receptors in the future.


Molecules ◽  
2022 ◽  
Vol 27 (2) ◽  
pp. 471
Author(s):  
Elisabetta Melloni ◽  
Elena Marchesi ◽  
Lorenzo Preti ◽  
Fabio Casciano ◽  
Erika Rimondi ◽  
...  

Chenodeoxycholic acid and ursodeoxycholic acid (CDCA and UDCA, respectively) have been conjugated with paclitaxel (PTX) anticancer drugs through a high-yield condensation reaction. Bile acid-PTX hybrids (BA-PTX) have been investigated for their pro-apoptotic activity towards a selection of cancer cell lines as well as healthy fibroblast cells. Chenodeoxycholic-PTX hybrid (CDC-PTX) displayed cytotoxicity and cytoselectivity similar to PTX, whereas ursodeoxycholic-PTX hybrid (UDC-PTX) displayed some anticancer activity only towards HCT116 colon carcinoma cells. Pacific Blue (PB) conjugated derivatives of CDC-PTX and UDC-PTX (CDC-PTX-PB and UDC-PTX-PB, respectively) were also prepared via a multistep synthesis for evaluating their ability to enter tumor cells. CDC-PTX-PB and UDC-PTX-PB flow cytometry clearly showed that both CDCA and UDCA conjugation to PTX improved its incoming into HCT116 cells, allowing the derivatives to enter the cells up to 99.9%, respect to 35% in the case of PTX. Mean fluorescence intensity analysis of cell populations treated with CDC-PTX-PB and UDC-PTX-PB also suggested that CDC-PTX-PB could have a greater ability to pass the plasmatic membrane than UDC-PTX-PB. Both hybrids showed significant lower toxicity with respect to PTX on the NIH-3T3 cell line.


2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Hai Hu ◽  
Wentao Shao ◽  
Qian Liu ◽  
Ning Liu ◽  
Qihan Wang ◽  
...  

AbstractCholesterol gallstone disease is a worldwide common disease. Cholesterol supersaturation in gallbladder bile is the prerequisite for its pathogenesis, while the mechanism is not completely understood. In this study, we find enrichment of gut microbiota (especially Desulfovibrionales) in patients with gallstone disease. Fecal transplantation of gut microbiota from gallstone patients to gallstone-resistant strain of mice can induce gallstone formation. Carrying Desulfovibrionales is associated with enhanced cecal secondary bile acids production and increase of bile acid hydrophobicity facilitating intestinal cholesterol absorption. Meanwhile, the metabolic product of Desulfovibrionales, H2S increase and is shown to induce hepatic FXR and inhibit CYP7A1 expression. Mice carrying Desulfovibrionales present induction of hepatic expression of cholesterol transporters Abcg5/g8 to promote biliary secretion of cholesterol as well. Our study demonstrates the role of gut microbiota, Desulfovibrionales, as an environmental regulator contributing to gallstone formation through its influence on bile acid and cholesterol metabolism.


2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Laura M. de Jong ◽  
Zhengzheng Zhang ◽  
Yvette den Hartog ◽  
Timothy J. P. Sijsenaar ◽  
Renata Martins Cardoso ◽  
...  

AbstractProtein arginine methyltransferase 3 (PRMT3) is a co-activator of liver X receptor capable of selectively modulating hepatic triglyceride synthesis. Here we investigated whether pharmacological PRMT3 inhibition can diminish the hepatic steatosis extent and lower plasma lipid levels and atherosclerosis susceptibility. Hereto, male hyperlipidemic low-density lipoprotein receptor knockout mice were fed an atherogenic Western-type diet and injected 3 times per week intraperitoneally with PRMT3 inhibitor SGC707 or solvent control. Three weeks into the study, SGC707-treated mice developed severe pruritus and scratching-associated skin lesions, leading to early study termination. SGC707-treated mice exhibited 50% lower liver triglyceride stores as well as 32% lower plasma triglyceride levels. Atherosclerotic lesions were virtually absent in all experimental mice. Plasma metabolite analysis revealed that levels of taurine-conjugated bile acids were ~ threefold increased (P < 0.001) in response to SGC707 treatment, which was paralleled by systemically higher bile acid receptor TGR5 signalling. In conclusion, we have shown that SGC707 treatment reduces hepatic steatosis and plasma triglyceride levels and induces pruritus in Western-type diet-fed LDL receptor knockout mice. These findings suggest that pharmacological PRMT3 inhibition can serve as therapeutic approach to treat non-alcoholic fatty liver disease and dyslipidemia/atherosclerosis, when unwanted effects on cholesterol and bile acid metabolism can be effectively tackled.


Nutrients ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 279
Author(s):  
Tiange Li ◽  
Yue Zhang ◽  
Jiajia Song ◽  
Lijun Chen ◽  
Min Du ◽  
...  

The effects of synbiotic yogurt supplemented with inulin on the pathological manifestations and gut microbiota–bile acid axis were investigated using a dehydroepiandrosterone (DHEA)-induced polycystic ovary syndrome (PCOS) mice model. Female C57BL/6J mice were injected subcutaneously with DHEA at a dose of 6 mg/100 g BW for 20 days to establish a PCOS mouse model. Then, the PCOS mice were treated with yogurt containing inulin (6% w/w) at 15 mL/kg BW for 24 days. Results showed that supplementation of synbiotic yogurt enriched with inulin to PCOS mice decreased the body weight gain, improved estrus cycles and ovary morphology, and reduced the levels of luteinizing hormone while increasing the levels of follicle-stimulating hormone and interleukin-22 in serum. At the genus level, synbiotic yogurt increased the relative abundance of Lactobacillus, Bifidobacterium, and Akkermansia. PICRUSt analysis indicated that KEGG pathways including bile acid biosynthesis were changed after inulin-enriched synbiotic yogurt supplementation. Synbiotic yogurt enriched with inulin also modulated the bile acid profiles. In conclusion, inulin-enriched synbiotic yogurt alleviated reproductive dysfunction and modulated gut microbiota and bile acid profiles in PCOS mice.


Metabolites ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 49
Author(s):  
Ambrin Farizah Babu ◽  
Ville Mikael Koistinen ◽  
Soile Turunen ◽  
Gloria Solano-Aguilar ◽  
Joseph F. Urban ◽  
...  

Sterols, bile acids, and acylcarnitines are key players in human metabolism. Precise annotations of these metabolites with mass spectrometry analytics are challenging because of the presence of several isomers and stereoisomers, variability in ionization, and their relatively low concentrations in biological samples. Herein, we present a sensitive and simple qualitative LC–MS/MS (liquid chromatography with tandem mass spectrometry) method by utilizing a set of pure chemical standards to facilitate the identification and distribution of sterols, bile acids, and acylcarnitines in biological samples including human stool and plasma; mouse ileum, cecum, jejunum content, duodenum content, and liver; and pig bile, proximal colon, cecum, heart, stool, and liver. With this method, we detected 24 sterol, 32 bile acid, and 27 acylcarnitine standards in one analysis that were separated within 13 min by reversed-phase chromatography. Further, we observed different sterol, bile acid, and acylcarnitine profiles for the different biological samples across the different species. The simultaneous detection and annotation of sterols, bile acids, and acylcarnitines from reference standards and biological samples with high precision represents a valuable tool for screening these metabolites in routine scientific research.


Biomedicines ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 111
Author(s):  
Armin Mooranian ◽  
Corina Mihaela Ionescu ◽  
Susbin Raj Wagle ◽  
Bozica Kovacevic ◽  
Daniel Walker ◽  
...  

A recent study showed an association between diabetes development and the bile acid lithocholic acid (LCA), while another study demonstrated positive biological effects of the conjugated bile acid, taurocholic acid (TCA), on pancreatic cells. Thus, this study aimed to encapsulate TCA with primary islets (graft) and study the biological effects of the graft, post-transplantation, in diabetic mice, including effects on LCA concentrations. Sixteen mature adult mice were made diabetic and randomly divided into two equal groups, control and test (transplanted encapsulated islets without or with TCA). Graft pharmaceutical features pre-transplantation, and biological effects including on LCA concentrations post-transplantation, were measured. TCA-microcapsules had an oval shape and similar size compared with the control. The treatment group survived longer, showed improved glucose and interleukin-6 concentrations, and lower LCA concentrations in plasma, large intestine, faeces, liver and spleen, compared with control. Results suggest that TCA incorporation with islets encapsulated graft exerted beneficial effects, but there was no direct and significant dependency between concentrations of interleukin-6 and LCA.


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