Endogenous Bile Acids Research Articles

Risk Factors of Cholangiocarcinogenesis in Parasitization of a Natural Focal Ecopathogen Helminth <i>Opisthorchis felineus</i>

Epidemiological researches, carried out by professor A.A. Shain in Ob-Irtysh basin of Tyumen region, have allowed to consider chronic opisthorchiasis as facultative liver precancer and develop the original concept of cholangiocarcinogenesis on the background of long-term invasion by trematode Opisthorchis felineus of hepatobiliary system of the body. According to this concept, the initiating role in cholangiocyte transformation belongs to endogenous factors secondary bile acids, having mutagenic/carcinogenic properties, which formation is mediated by helminthosis-related exogenous intestinal microflora in intrahepatic bile ducts. Obtained data confirmed content of endogenous carcinogenic factors secondary bile acids in duct bile of chronic opistorchosis patients. Cholestasis, caused by long-term parasitization of helminth Opisthorchis felineus in hepatobiliary system of the body, mediates formation of the host promoter factors, contributing to cholangiocarcinoma progression. These include: high concentration in duct bile of bile acids, products of helminths activity and lipid peroxidation of somatic cell membranes. Promoter factors of cholangiocanerogenesis are also disorders of cholangiocyte membranes structure, tissue regulation of their regeneration, DNA repair and anti-tumorigenic protection of the body. The results of the study confirm the concept of occurrence and development of the process of cholangiocarcinogenesis in chronic opistorchosis infestation, proposed by Professor A.A. Shain and allow to reasonably develop approaches to the correction of homeostasis regulation systems of the organism in the specified helminthiasis. Which also determines the secondary prevention of malignant process in ductal epithelium of hepatobiliary system in posthelminthic period.

Increased concentrations of conjugated bile acids are associated with osteoporosis in PSC patients

Primary sclerosing cholangitis (PSC) is an idiopathic cholestatic liver disease characterized by chronic inflammation and progressive fibrosis of intra- and extrahepatic bile ducts. Osteoporosis is a frequent comorbidity in PSC, and we could previously demonstrate that IL17-dependent activation of bone resorption is the predominant driver of bone loss in PSC. Since we additionally observed an unexpected heterogeneity of bone mineral density in our cohort of 238 PSC patients, the present study focused on a comparative analysis of affected individuals with diagnosed osteoporosis (PSCOPO, n = 10) or high bone mass (PSCHBM, n = 7). The two groups were not distinguishable by various baseline characteristics, including liver fibrosis or serum parameters for hepatic function. In contrast, quantification of serum bile acid concentrations identified significant increases in the PSCOPO group, including glycoursodeoxycholic acid (GUDCA), an exogenous bile acid administered to both patient groups. Although cell culture experiments did not support the hypothesis that an increase in circulating bile levels is a primary cause of PSC-associated osteoporosis, the remarkable differences of endogenous bile acids and GUDCA in the serum of PSCOPO patients strongly suggest a yet unknown impairment of biliary metabolism and/or hepatic bile acid clearance in this patient subgroup, which is independent of liver fibrosis.

N-(4-[18F]fluorobenzyl)cholylglycine, a potential tracer for positron emission tomography of enterohepatic circulation and drug-induced inhibition of ileal bile acid transport. A proof-of-concept PET/CT study in pigs

IntroductionEnterohepatic circulation (EHC) of conjugated bile acids is an important physiological process crucial for bile acids to function as detergents and signal carriers. Perturbation of the EHC by disease or drugs may lead to serious and life-threatening liver and gastrointestinal disorders. In this proof-of-concept study in pigs, we investigate the potential of N-(4-[18F]fluorobenzyl)cholylglycine ([18F]FBCGly) as tracer for quantitative positron emission tomography (PET) of the EHC of conjugated bile acids. MethodsThe biodistribution of [18F]FBCGly was investigated by PET/CT in domestic pigs following intravenous and intraileal administration of the tracer. Hepatic kinetics were estimated from PET and blood data using a 2-tissue compartmental model and dual-input of [18F]FBCGly. The ileal uptake of [18F]FBCGly was investigated with co-injection of nifedipine and endogenous cholyltaurine. Dosimetry was estimated from the PET data using the Olinda 2.0 software. Blood, bile and urine samples were analyzed for possible fluorine-18 labelled metabolites of [18F]FBCGly. Results[18F]FBCGly was rapidly taken up by the liver and excreted into bile, and underwent EHC without being metabolized. Both nifedipine and endogenous cholyltaurine inhibited the ileal uptake of [18F]FBCGly. The flow-dependent hepatic uptake clearance was estimated to median 1.2 mL blood/min/mL liver tissue. The mean residence time of [18F]FBCGly in hepatocytes was 4.0 ± 1.1 min. Critical organs for [18F]FBCGly were the gallbladder wall (0.94 mGy/MBq) and the small intestine (0.50 mGy/MBq). The effective dose for [18F]FBCGly was 36 μSv/MBq. ConclusionWe have shown that [18F]FBCGly undergoes EHC in pigs without being metabolized and that its ileal uptake is inhibited by nifedipine and endogenous bile acids. Combined with our previous findings in rats, we believe that [18F]FBCGly has potential as PET tracer for assessment of EHC of conjugated bile acids under physiological conditions as well as conditions with perturbed hepatic and ileal bile acid transport.

A rapid and standardized workflow for functional assessment of bacterial biosensors in fecal samples.

Gut metabolites are pivotal mediators of host-microbiome interactions and provide an important window on human physiology and disease. However, current methods to monitor gut metabolites rely on heavy and expensive technologies such as liquid chromatography-mass spectrometry (LC-MS). In that context, robust, fast, field-deployable, and cost-effective strategies for monitoring fecal metabolites would support large-scale functional studies and routine monitoring of metabolites biomarkers associated with pathological conditions. Living cells are an attractive option to engineer biosensors due to their ability to detect and process many environmental signals and their self-replicating nature. Here we optimized a workflow for feces processing that supports metabolite detection using bacterial biosensors. We show that simple centrifugation and filtration steps remove host microbes and support reproducible preparation of a physiological-derived media retaining important characteristics of human feces, such as matrix effects and endogenous metabolites. We measure the performance of bacterial biosensors for benzoate, lactate, anhydrotetracycline, and bile acids, and find that they are highly sensitive to fecal matrices. However, encapsulating the bacteria in hydrogel helps reduce this inhibitory effect. Sensitivity to matrix effects is biosensor-dependent but also varies between individuals, highlighting the need for case-by-case optimization for biosensors’ operation in feces. Finally, by detecting endogenous bile acids, we demonstrate that bacterial biosensors could be used for future metabolite monitoring in feces. This work lays the foundation for the optimization and use of bacterial biosensors for fecal metabolites monitoring. In the future, our method could also allow rapid pre-prototyping of engineered bacteria designed to operate in the gut, with applications to in situ diagnostics and therapeutics.

Mesenchymal Stromal Cells Overexpressing Farnesoid X Receptor Exert Cardioprotective Effects Against Acute Ischemic Heart Injury by Binding Endogenous Bile Acids (Adv. Sci. 24/2022)

Mesenchymal Stromal Cells In article number 2200431, Wenjun Yan, Ling Tao, and co-workers report a novel strategy for improving the curative effect of mesenchymal stromal cell (MSC)-based therapy for myocardial infarction that is achieved by bile acid- arnesoid X receptor (FXR) axis activation. FXR overexpression in MSC facilitates the response of MSC to endogenous bile acid signals, thus enhancing the survival and paracrine angiogenesis of MSC.

Lack of an Effect of Polysorbate 80 on Intestinal Drug Permeability in Humans.

Despite no broad, direct evidence in humans, there is a potential concern that surfactants alter active or passive drug intestinal permeation to modulate oral drug absorption. The purpose of this study was to investigate the impact of the surfactant polysorbate 80 on active and passive intestinal drug absorption in humans. The human (n = 12) pharmacokinetics (PK) of three probe substrates of intestinal absorption, valacyclovir, chenodeoxycholic acid (CDCA), and enalaprilat, were assessed. Endogenous bile acid levels were assessed as a secondary measure of transporter and microbiota impact. Polysorbate 80 did not inhibit peptide transporter 1 (PepT1)- or apical sodium bile acid transporter (ASBT)-mediated PK of valacyclovir and CDCA, respectively. Polysorbate 80 did not increase enalaprilat absorption. Modest increases in unconjugated secondary bile acid Cmax ratios suggest a potential alteration of the in vivo intestinal microbiota by polysorbate 80. Polysorbate 80 did not alter intestinal membrane fluidity or cause intestinal membrane disruption. This finding supports regulatory relief of excipient restrictions for Biopharmaceutics Classification System-based biowaivers.

Tauroursodeoxycholic acid inhibits TGF-β1-induced renal fibrosis markers in cultured renal mesangial cells by regulating endoplasmic reticulum stress.

Chronic kidney disease (CKD) has a worldwide prevalence of higher than 10% with an increasing mortality rate. As it involves the deterioration of renal function, it represents a serious risk to human health and, if left untreated, significantly lowers the quality of the patient's life. CKD is characterized by renal fibrosis. Studies have shown that transforming growth factor β1 (TGF-β1), a key driving factor of renal fibrosis, is closely related to the activation of renal fibrosis pathways such as endoplasmic reticulum stress (ERS). Tauroursodeoxycholic acid (TUDCA), an endogenous bile acid derivative, can effectively inhibit endogenous ERS. Here, we explored the effects and actions of TUDCA on renal fibrosis by establishing a renal mesangial cell (RMC) model. The RMC was stimulated with TGF-β1, and PCR and western blotting were used to detect the expression of ERS-related chaperone proteins and fibrotic indicators. The expression of glucose-regulated protein 78 (GRP78) was silenced in RMC cells to investigate the role of GRP78 in renal fibrosis. Finally, PCR and western blotting were used to detect the effects of TUDCA on the expression of GRP78, C/EBP homologous protein (CHOP), α-smooth muscle actin (α-SMA), and fibronectin (FN) in the TGF-β1-stimulated RMCs. The results showed that TUDCA significantly downregulated TGF-β1-induced levels of GRP78, CHOP, α-SMA and FN in RMCs. In addition, downregulation of GRP78 inhibited the expression of FN and α-SMA in the RMCs. In conclusion, downregulation of GRP78 and CHOP expression is one of the mechanisms by which TUDCA inhibits TGF-β1-induced renal mesangial cell fibrosis.

Physiologically-based modeling of cholate disposition in beagle dog with and without treatment of the liver transporter inhibitor simeprevir

BSEP inhibition is one risk factor for Drug-Induced Liver Injury (DILI). While in vitro screening of BSEP inhibition may prevent compounds with BSEP liability from progressing into the clinic, these in vitro data alone can result in false-positives and as such a specific in vivo biomarker would further enhance our BSEP inhibition de-risking strategy. Measurement of endogenous bile acids as biomarkers of BSEP inhibition in vivo is complicated by several factors, including drugs that inhibit BSEP can also inhibit other bile acid transporters such as NTCP. Here, we developed a novel translational framework, including an in vivo biomarker with a corresponding mechanistic model, and attempted to decouple the effect of liver sinusoidal uptake inhibition from efflux inhibition on bile acid disposition in the beagle dog. Specifically, we hypothesized that the change of a stable isotope-labeled (SIL) bile acid tracer’s exposure would yield a toxicodynamic signal that can provide insight into BSEP inhibition and ensuing bile salt accumulation. For this purpose we dosed the stable isotope-labeled cholic acid (13C-CA) and taurocholic acid (D4-TCA) as biomarker tracers in dogs, with and without the liver transporter inhibitor simeprevir, and determined the plasma and bile exposure of 13C-CA, 13C-TCA, D4-CA and D4-TCA in vivo. Key bile acid clearance and transporter inhibition parameters were determined in vitro. We developed a novel Physiologically Based Pharmacokinetic model (PBPK) to integrate the mechanistic physiological understanding, literature knowledge, and in vitro laboratory data to model bile acid disposition. Using modeling and simulation, we provided an increased mechanistic understanding of how to use plasma bile acid tracer data to inform on potential liver transporters inhibition and limitations to in vivo translation. The novel translational framework can enhance the future BSEP inhibition de-risking strategy, particularly if the experimental confounders to studying kinetics in dog hepatocytes in vitro models are solved.

Interruption of bile acid uptake by hepatocytes after acetaminophen overdose ameliorates hepatotoxicity

Background & AimsAcetaminophen (APAP) overdose remains a frequent cause of acute liver failure, which is generally accompanied by increased levels of serum bile acids (BAs). However, the pathophysiological role of BAs remains elusive. Herein, we investigated the role of BAs in APAP-induced hepatotoxicity.MethodsWe performed intravital imaging to investigate BA transport in mice, quantified endogenous BA concentrations in the serum of mice and patients with APAP overdose, analyzed liver tissue and bile by mass spectrometry and MALDI-mass spectrometry imaging, assessed the integrity of the blood-bile barrier and the role of oxidative stress by immunostaining of tight junction proteins and intravital imaging of fluorescent markers, identified the intracellular cytotoxic concentrations of BAs, and performed interventions to block BA uptake from blood into hepatocytes.ResultsPrior to the onset of cell death, APAP overdose causes massive oxidative stress in the pericentral lobular zone, which coincided with a breach of the blood-bile barrier. Consequently, BAs leak from the bile canaliculi into the sinusoidal blood, which is then followed by their uptake into hepatocytes via the basolateral membrane, their secretion into canaliculi and repeated cycling. This, what we termed ‘futile cycling’ of BAs, led to increased intracellular BA concentrations that were high enough to cause hepatocyte death. Importantly, however, the interruption of BA re-uptake by pharmacological NTCP blockage using Myrcludex B and Oatp knockout strongly reduced APAP-induced hepatotoxicity.ConclusionsAPAP overdose induces a breach of the blood-bile barrier which leads to futile BA cycling that causes hepatocyte death. Prevention of BA cycling may represent a therapeutic option after APAP intoxication.Lay summaryOnly one drug, N-acetylcysteine, is approved for the treatment of acetaminophen overdose and it is only effective when given within ∼8 hours after ingestion. We identified a mechanism by which acetaminophen overdose causes an increase in bile acid concentrations (to above toxic thresholds) in hepatocytes. Blocking this mechanism prevented acetaminophen-induced hepatotoxicity in mice and evidence from patients suggests that this therapy may be effective for longer periods after ingestion compared to N-acetylcysteine.

Dietary Inhibitors of CYP3A4 Are Revealed Using Virtual Screening by Using a New Deep-Learning Classifier.

CYP3A4 is the main human enzyme responsible for phase I metabolism of dietary compounds, prescribed drugs and xenobiotics, steroid hormones, and bile acids. The inhibition of CYP3A4 activity might impair physiological mechanisms, including the endocrine system and response to drug admission. Here, we aimed to discover new CYP3A4 inhibitors from food and dietary supplements. A deep-learning model was built that classifies compounds as either an inhibitor or noninhibitor, with a high specificity of 0.997. We used this classifier to virtually screen ∼60,000 dietary compounds. Of the 115 identified potential inhibitors, only 31 were previously suggested. Many herbals, as predicted here, might cause impaired metabolism of drugs, and endogenous hormones and bile acids. Additionally, by applying Lipinski’s rules of five, 17 compounds were also classified as potential intestine local inhibitors. New CYP3A4 inhibitors predicted by the model, bilobetin and picropodophyllin, were assayed in vitro.

The Benevolent Bile: Bile Acids as Stimulants of Liver Regeneration

The Benevolent Bile: Bile Acids as Stimulants of Liver Regeneration

Effect of Suanzaoren Decoction on molecular levels of bile acids in serum, liver, and ileum of insomnia mice

To explore the mechanism of Suanzaoren Decoction in the treatment of insomnia from endogenous bile acid regulation, the present study investigated the hepatoprotective effect of Suanzaoren Decoction and the molecular changes of bile acids in the serum, liver, and ileum of insomnia model mice and Suanzaoren Decoction treated mice. The insomnia model in mice was established by the sleep deprivation method. After Suanzaoren Decoction(48.96 mg·kg~(-1)·d~(-1)) intervention by gavage for 7 days, the related indicators, such as water consumption, food intake, body weight, aspartate aminotransferase(AST), alanine transaminase(ALT), and total bile acid(TBA) were detected, and the pathological changes of the liver and ileum were observed. The molecular levels and distribution of 23 bile acids in the serum, liver, and ileum were analyzed by UPLC-MS/MS combined with principal component analysis(PCA) and partial least squares discriminant analysis(PLS-DA). The results showed that Suanzaoren Decoction could improve the decreased water consumption and food intake, weight loss, and increased AST and ALT in the model group, and effectively reverse the injury and inflammation in the liver and ileum. The bile acids in the liver of the insomnia model mice were in the stage of decompensation, and the bile acids in the serum, liver, and ileum of the mice decreased or increased. Suanzaoren Decoction could regulate the anomaly of some bile acids back to normal. Seven bile acids including glycoursodeoxycholic acid(GUDCA), glycodesoxycholic acid(GDCA), tauro-α-MCA(T-α-MCA), α-MCA, taurodeoxycholate(TDCA), T-β-MCA, and LCA were screened out as the main discriminant components by PLS-DA. It is concluded that Suanzaoren Decoction possesses the hepatoprotective effect and bile acids could serve as the biochemical indicators to evaluate the drug efficacy in the treatment of abnormal liver functions caused by insomnia. The mechanism of Suanzao-ren Decoction in soothing the liver, resolving depression, tranquilizing the mind, and improving sleep may be related to the molecular regulation of bile acid signals.

Hepatotoxicity of cantharidin is associated with the altered bile acid metabolism.

Cantharidin (CTD) is an effective antitumor agent. However, it exhibits significant hepatotoxicity, the mechanism of which remains unclear. In this study, biochemical and histopathological analyses complemented with ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS)-based targeted metabolomic analysis of bile acids (BAs) were employed to investigate CTD-induced hepatotoxicity in rats. Sixteen male and female Sprague-Dawley rats were randomly divided into two groups: control and CTD (1.0mg/kg) groups. Serum and liver samples were collected after 28 days of intervention. Biochemical, histopathological, and BA metabolomic analyses were performed for all samples. Further, the key biomarkers of CTD-induced hepatotoxicity were identified via multivariate and metabolic pathway analyses. In addition, metabolite-gene-enzyme network and Kyoto Encyclopedia of Genes and Genomes pathway analyses were used to identify the signaling pathways related to CTD-induced hepatotoxicity. The results revealed significantly increased levels of biochemical indices (alanine aminotransferase, aspartate aminotransferase, and total bile acid). Histopathological analysis revealed that the hepatocytes were damaged. Further, 20 endogenous BAs were quantitated via UHPLC-MS/MS, and multivariate and metabolic pathway analyses of BAs revealed that hyocholic acid, cholic acid, and chenodeoxycholic acid were the key biomarkers of CTD-induced hepatotoxicity. Meanwhile, primary and secondary BA biosynthesis and taurine and hypotaurine metabolism were found to be associated with the mechanism by which CTD induced hepatotoxicity in rats. This study provides useful insights for research on the mechanism of CTD-induced hepatotoxicity.

Characterization of endogenous bile acid composition in individuals with cold-activated brown adipose tissue

IntroductionBile acid signaling has been suggested to promote BAT activity in various experimental models. However, little is known if and how physiologic bile acid metabolism is linked to BAT function in humans. Here we investigated the association between BAT activity and circulating bile acid concentrations in lean and obese individuals. MethodsBAT 18F-fluorodeoxyglucose uptake was measured after a standardized cooling protocol by positron emission tomography/computed tomography. Cold-induced thermogenesis was assessed by indirect calorimetry. Fasting bile acid concentrations were determined by high performance liquid chromatography–high-resolution mass spectrometry. ResultsIn a cohort of 24 BAT-negative and 20 BAT-positive individuals matched by age, sex, and body mass index, circulating bile acid levels were similar between groups except for higher ursodeoxycholic acid and a trend towards a lower 12α-OH/non-12α-OH bile acid ratio in lean participants with active BAT compared to those without. Moreover, the 12α-OH/non-12α-OH ratio, a marker of CYP8B1 activity, correlated negatively with BAT volume and activity. ConclusionFasting concentrations of major bile acids are not associated with cold-induced BAT activity in humans. However, the inverse association between BAT activity and 12α-OH/non-12α-OH ratio may suggest CYP8B1 as a potential new target in BAT function and warrants additional investigation.

Genetic Disorders of Bile Acid Transport.

Genetic Disorders of Bile Acid Transport.

A bilirubin-derived nanomedicine attenuates the pathological cascade of pulmonary fibrosis

Pulmonary fibrosis is an irreparable and life-threatening disease with only limited therapeutic options. The recent outbreak of COVID-19 has caused a sharp rise in the incidence of pulmonary fibrosis owing to SARS-CoV-2 infection-mediated acute respiratory distress syndrome (ARDS). The considerable oxidative damage caused by locally infiltrated immune cells plays a crucial role in ARDS, suggesting the potential use of antioxidative therapeutics. Here, we report the therapeutic potential of nanoparticles derived from the endogenous antioxidant and anti-inflammatory bile acid, bilirubin (BRNPs), in treating pulmonary fibrosis in a bleomycin-induced mouse model of the disease. Our results demonstrate that BRNPs can effectively reduce clinical signs in mice, as shown by histological, disease index evaluations, and detection of biomarkers. Our findings suggest that BRNPs, with their potent antioxidant and anti-inflammatory effects, long blood circulation half-life, and preferential accumulation at the inflamed site, are potentially a viable clinical option for preventing Covid-19 infection-associated pulmonary fibrosis.

Effects of Manipulating Circulating Bile Acid Concentrations on Postprandial GLP-1 Secretion and Glucose Metabolism After Roux-en-Y Gastric Bypass.

BackgroundAltered bile acid (BA) turnover has been suggested to be involved in the improved glucose regulation after Roux-en-Y gastric bypass (RYGB), possibly via stimulation of GLP-1 secretion. We investigated the role of exogenous as well as endogenous BAs for GLP-1 secretion after RYGB by administering chenodeoxycholic acid (CDCA) and the BA sequestrant colesevelam (COL) both in the presence and the absence of a meal stimulus.MethodsTwo single-blinded randomized cross-over studies were performed. In study 1, eight RYGB operated participants ingested 200 ml water with 1) CDCA 1.25 g or 2) CDCA 1.25 g + colesevelam 3.75 g on separate days. In study 2, twelve RYGB participants ingested on separate days a mixed meal with addition of 1) CDCA 1.25 g, 2) COL 3.75 g or 3) COL 3.75 g × 2, or 4) no additions.ResultsIn study 1, oral intake of CDCA increased circulating BAs, GLP-1, C-peptide, glucagon, and neurotensin. Addition of colesevelam reduced all responses. In study 2, addition of CDCA enhanced meal-induced increases in plasma GLP-1, glucagon and FGF-19 and lowered plasma glucose and C-peptide concentrations, while adding colesevelam lowered circulating BAs but did not affect meal-induced changes in plasma glucose or measured gastrointestinal hormones.ConclusionIn RYGB-operated persons, exogenous CDCA enhanced meal-stimulated GLP-1 and glucagon secretion but not insulin secretion, while the BA sequestrant colesevelam decreased CDCA-stimulated GLP-1 secretion but did not affect meal-stimulated GLP-1, C-peptide or glucagon secretion, or glucose tolerance. These findings suggest a limited role for endogenous bile acids in the acute regulation of postprandial gut hormone secretion or glucose metabolism after RYGB.

Ecdysteroid metabolism in mammals: The fate of ingested 20-hydroxyecdysone in mice and rats

Phytoecdysteroids are molecules derived from sterol metabolism and found in many plants. They display a wide array of pharmacological effects on mammals (e.g. anabolic, anti-diabetic). Although these effects have been long established, the molecular targets involved remain to be identified. Like endogenous steroid hormones and bile acids, which are biochemically related, ingested or injected phytoecdysteroids undergo a set of reactions in mammals leading to the formation of numerous metabolites, only some of which have been so far identified, and it is presently unknown whether they represent active metabolites or inactivation products. In the large intestine, ecdysteroids undergo efficient 14-dehydroxylation. Other changes (reductions, epimerization, side-chain cleavage) are also observed, but whether these occur in the liver and/or large intestine is not known. The purpose of this study was to investigate the pharmacokinetics of 20-hydroxyecdysone (20E), the most common phytoecdysteroid, when administered to mice and rats, using, when required, tritium-labelled molecules to permit metabolic tracking. Bioavailability, the distribution of radioactivity and the kinetics of formation of metabolites were followed for 24−48 hours after ingestion and qualitative and quantitative analyses of circulating and excreted compounds were performed. In mice, the digestive tract always contains the majority of the ingested 20E. Within 30 min after ingestion, 20E reaches the large intestine, where microorganisms firstly remove the 14-hydroxyl group and reduce the 6-one. Then a very complex set of metabolites (not all of which have yet been identified) appears, which correspond to poststerone derivatives formed in the liver. We have observed that these compounds (like bile acids) undergo an entero-hepatic cycle, involving glucuronide conjugation in the liver and subsequent deconjugation in the intestine. Despite the very short half-life of ecdysteroids in mammals, this entero-hepatic cycle helps to maintain their plasma levels at values which, albeit low (≤0.2 μM), would be sufficient to evoke several pharmacological effects. Similar 20E metabolites were observed in mice and rats; they include in particular 14-deoxy-20E, poststerone and 14-deoxypoststerone and their diverse reduction products; the major products of this metabolism have been unambiguously identified. The major sites of metabolism of exogenous ecdysteroids in mammals are the large intestine and the liver. The entero-hepatic cycle contributes to the metabolism and to maintaining a low, but pharmacologically significant, concentration of ecdysteroids in the blood for ca. 24 h after ingestion. These data, together with parallel in vitro experiments provide a basis for the identification of 20E metabolite(s) possibly involved in the physiological effects associated with ecdysteroids in mammals.

Effects of Bile Acids on Growth Performance and Lipid Metabolism during Chronic Heat Stress in Broiler Chickens.

Simple SummaryThe negative impacts of heat stress (HS) on growth performance and lipid metabolism have been reported, but there are still no effective nutritional strategies to alleviate heat stress. Bile acids are new for their antioxidative properties and regulatory effect on lipid metabolism. This study was carried out to evaluate the growth performance and lipid metabolism in chickens under heat stress when fed with bile acid supplements in their diet. The results showed that mild heat stress (32 °C) induced hepatic lipogenic gene (hepatic SREBP-1c) expressions and lipid deposition, without obvious tissue damage in broilers. Dietary supplementation of bile acid could decrease hepatic lipid deposition without affecting endogenous bile acid biosynthesis. Therefore, bile acid supplements can benefit broiler chickens during high ambient temperatures, serving as a new nutritional strategy against heat stress.This study aimed to investigate whether dietary bile acid (BA) supplements can improve growth performance and lipid metabolism in heat-stressed broiler chickens. A total of 288 Arbor Acres broilers were blocked by BW and then randomly allocated into 4 treatments at 21 days of age. Birds reared under 32 °C had a higher cloacal temperature (p = 0.01), faster respiratory rate (p < 0.001), and a greatly reduced average daily feed intake (ADFI, p = 0.016), average daily gain (ADG, p = 0.006), final body weight (FBW, p = 0.008), and feed conversion rate (FCR, p = 0.004). In heat stress (HS) birds, the breast muscle rate (p = 0.006) and pH 24 h postmortem (p = 0.065) were lower, and the shear force was higher (p = 0.027). Dietary BA supplements tended to increase the breast muscle rate (p = 0.075) without affecting the growth performance and serum lipids (p > 0.05). Serum total bile acid (TBA) was roughly duplicated after BA supplements (p = 0.001). In the liver, total cholesterol was lower (p = 0.046), and triglycerides were higher (p = 0.04) in the HS birds, whereas the expression of SREBP-1c showed an increasing trend (p = 0.06). In contrast, dietary BA decreased triglycerides and the expressions of hepatic SREBP-1c and FAS in the liver (p < 0.05). In summary, mild HS causes hepatic lipid accumulation without obvious tissue damages, whereas BA has positive effects on relieving abnormal lipid metabolism, indicating that BA as a nutritional strategy has a certain potential in alleviating HS.

The role of ursodeoxycholic acid in the treatment of intrahepatic cholestasis in pregnant women after ART

Intrahepatic cholestasis of pregnancy (IHCP) is of significant practical interest as this pathology is a borderline case between obstetric, infectious and hepatic pathology. The issues of etiology, pathogenesis, risk factors triggering intrahepatic cholestasis, the principles of its treatment and prevention are still an object of debate. At present, ursodeoxycholic acid (UDCA) is considered to be the medicine of choice for the treatment of intrahepatic cholestasis of pregnancy. The peculiarity of this medicine lies in its 4 mechanisms of action: replacement of toxic endogenous bile acids, cytoprotective action for hepatocytes and cholangiocytes, immunomodulation and choleretic action [3]. To test the efficiency of the suggested drug, we selected 71 women who got pregnant owing to ART and who presented a high risk of IHCP at the first prognostication stage. By way of randomization, they were divided into 2 groups: the basic group – 29 patients, who were treated with the recommended complex of therapy and prophylaxis, and the comparison group – 42 pregnant women, whose pregnancy was managed in accordance with the WHO guidelines. The recommended ursodeoxycholic acid has enabled a more effective normalization of biochemical indicators associated with IHCP (reduction of the levels of total bilirubin, bile acids, ALT, AP and total cholesterol in terms of the low-density and the very-low-density lipoprotein fraction) and a significant decrease in the incidence of complications of pregnancy.