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The NTCP-inhibitor Myrcludex B: Effects on Bile Acid Disposition and Tenofovir Pharmacokinetics.
Blank, A, Eidam, A, Haag, M, Hohmann, N, Burhenne, J, Schwab, M, van de Graaf, S, Meyer, MR, Maurer, HH, Meier, K, et al
Clinical pharmacology and therapeutics. 2018;(2):341-348
Abstract
Myrcludex B acts as a hepatitis B and D virus entry inhibitor blocking the sodium taurocholate cotransporting polypeptide (SLC10A1). We investigated the effects of myrcludex B on plasma bile acid disposition, tenofovir pharmacokinetics, and perpetrator characteristics on cytochrome P450 (CYP) 3A. Twelve healthy volunteers received 300 mg tenofovir disoproxil fumarate orally and 10 mg subcutaneous myrcludex B. Myrcludex B increased total plasma bile acid exposure 19.2-fold without signs of cholestasis. The rise in conjugated bile acids was up to 124-fold (taurocholic acid). Coadministration of tenofovir with myrcludex B revealed no relevant changes in tenofovir pharmacokinetics. CYP3A activity slightly but significantly decreased by 29% during combination therapy. Myrcludex B caused an asymptomatic but distinct rise in plasma bile acid concentrations and had no relevant impact on tenofovir pharmacokinetics. Changes in CYP3A activity might be due to alterations in bile acid signaling. Long-term effects of elevated bile acids will require critical evaluation.
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2.
New therapies target the toxic consequences of cholestatic liver disease.
Jansen, PLM
Expert review of gastroenterology & hepatology. 2018;(3):277-285
Abstract
In most cholestatic liver diseases the primary cholestasis-causing lesions are located in the biliary tree and may be of (auto)immune origin. Bile salts are responsible for the secondary toxic consequences. Bile salt and nuclear hormone directed therapies primarily aim at improving this secondary toxic injury. In primary biliary cholangitis, trials show statistically significant responses on biochemical endpoints. Preclinical studies suggest that FXR- and PPAR-agonists, inhibitors of the apical sodium-dependent bile salt transporter (ASBT-inhibitors) and the C23 UDCA derivative nor-UDCA are promising agents for the treatment of primary sclerosing cholangitis (PSC). Area covered: Pharmaceuticals that interfere with bile salt signaling in humans for the treatment of chronic cholestatic liver disease are reviewed. Expert commentary: Nuclear hormone receptors, bile salt transport proteins and receptors provide targets for novel therapies of cholestatic liver disease. These drugs show positive results on biochemical endpoints. For histological endpoints, survival and transplant-free survival, long-term trials are needed. For relief of symptoms, such as fatigue and pruritus, these drugs have yet to prove their value.
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3.
Bile acid metabolism and signaling: potential therapeutic target for nonalcoholic fatty liver disease.
Lin, CH, Kohli, R
Clinical and translational gastroenterology. 2018;(6):164
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4.
Effects of supplemented isoenergetic diets varying in cereal fiber and protein content on the bile acid metabolic signature and relation to insulin resistance.
Weickert, MO, Hattersley, JG, Kyrou, I, Arafat, AM, Rudovich, N, Roden, M, Nowotny, P, von Loeffelholz, C, Matysik, S, Schmitz, G, et al
Nutrition & diabetes. 2018;(1):11
Abstract
Bile acids (BA) are potent metabolic regulators influenced by diet. We studied effects of isoenergetic increases in the dietary protein and cereal-fiber contents on circulating BA and insulin resistance (IR) in overweight and obese adults. Randomized controlled nutritional intervention (18 weeks) in 72 non-diabetic participants (overweight/obese: 29/43) with at least one further metabolic risk factor. Participants were group-matched and allocated to four isoenergetic supplemented diets: control; high cereal fiber (HCF); high-protein (HP); or moderately increased cereal fiber and protein (MIX). Whole-body IR and insulin-mediated suppression of hepatic endogenous glucose production were measured using euglycaemic-hyperinsulinemic clamps with [6-62H2] glucose infusion. Circulating BA, metabolic biomarkers, and IR were measured at 0, 6, and 18 weeks. Under isoenergetic conditions, HP-intake worsened IR in obese participants after 6 weeks (M-value: 3.77 ± 0.58 vs. 3.07 ± 0.44 mg/kg/min, p = 0.038), with partial improvement back to baseline levels after 18 weeks (3.25 ± 0.45 mg/kg/min, p = 0.089). No deleterious effects of HP-intake on IR were observed in overweight participants. HCF-diet improved IR in overweight participants after 6 weeks (M-value 4.25 ± 0.35 vs. 4.81 ± 0.31 mg/kg/min, p = 0.016), but did not influence IR in obese participants. Control and MIX diets did not influence IR. HP-induced, but not HCF-induced changes in IR strongly correlated with changes of BA profiles. MIX-diet significantly increased most BA at 18 weeks in obese, but not in overweight participants. BA remained unchanged in controls. Pooled BA concentrations correlated with fasting fibroblast growth factor-19 (FGF-19) plasma levels (r = 0.37; p = 0.003). Higher milk protein intake was the only significant dietary predictor for raised total and primary BA in regression analyses (total BA, p = 0.017; primary BA, p = 0.011). Combined increased intake of dietary protein and cereal fibers markedly increased serum BA concentrations in obese, but not in overweight participants. Possible mechanisms explaining this effect may include compensatory increases of the BA pool in the insulin resistant, obese state; or defective BA transport.
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5.
Familial Hypercholesterolemia in Children and Adolescents: Diagnosis and Treatment.
Maliachova, O, Stabouli, S
Current pharmaceutical design. 2018;(31):3672-3677
Abstract
Familial hypercholesterolemia is a hereditary genetic disorder predisposing in premature atherosclerosis and cardiovascular complications. Early diagnosis as well as effective treatment strategies in affected children are challenges among experts. Universal screening and cascade screening among families with familial hypercholesterolemia are being controversially discussed. Diagnosis of familial hypercholesterolemia in children and adolescents is usually based on clinical phenotype upon LDL-C levels and family history of premature cardiovascular and/or elevated LDL-C. Treatment approaches for familial hypercholesterolemia in the pediatric population are multidisciplinary and aim to reduce total cardiovascular risk. The most widely recommended and effective pharmacotherapy in the pediatric age group is currently statins. Ezetimibe and bile acid sequestrants are usually used as second-line agents. New therapeutic approaches, such as mipomersen and PCSK9 inhibitors seem promising. The main gap of evidence remains the lack of longitudinal follow up studies investigating cardiovascular outcomes, side effects, and effectiveness of treatment starting from childhood. Evidence would be expected in the near future by cohort and registry studies.
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6.
Nutritional Modulation of Innate Immunity: The Fat-Bile-Gut Connection.
Chevre, R, Silvestre-Roig, C, Soehnlein, O
Trends in endocrinology and metabolism: TEM. 2018;(10):686-698
Abstract
Altered nutritional behavior in Western societies has unleashed numerous metabolic disorders, intimately linked to profound disruptions of the immune system. Here we summarize how nutrition modulates innate immunity. We outline recent findings regarding nutrient signaling and we particularly focus on the collateral impact of nutrition on the microbiome and on the bile acid (BA) pool. We discuss how the integration of postprandial signals by the gut microbiota, along with the absorption routes of metabolites, differentially affects immune niches to orchestrate immune responses. Finally, we discuss the potential consequences of these signals in the light of trained immunity. A better understanding of nutrition signaling will permit the optimization of therapeutic and dietary strategies against the arising immune disorders.
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7.
Obeticholic acid for severe bile acid diarrhea with intestinal failure: A case report and review of the literature.
Hvas, CL, Ott, P, Paine, P, Lal, S, Jørgensen, SP, Dahlerup, JF
World journal of gastroenterology. 2018;(21):2320-2326
Abstract
Bile acid diarrhea results from excessive amounts of bile acids entering the colon due to hepatic overexcretion of bile acids or bile acid malabsorption in the terminal ileum. The main therapies include bile acid sequestrants, such as colestyramine and colesevelam, which may be given in combination with the opioid receptor agonist loperamide. Some patients are refractory to conventional treatments. We report the use of the farnesoid X receptor agonist obeticholic acid in a patient with refractory bile acid diarrhea and subsequent intestinal failure. A 32-year-old woman with quiescent colonic Crohn's disease and a normal terminal ileum had been diagnosed with severe bile acid malabsorption and complained of watery diarrhea and fatigue. The diarrhea resulted in hypokalemia and sodium depletion that made her dependent on twice weekly intravenous fluid and electrolyte infusions. Conventional therapies with colestyramine, colesevelam, and loperamide had no effect. Second-line antisecretory therapies with pantoprazole, liraglutide, and octreotide also failed. Third-line treatment with obeticholic acid reduced the number of stools from an average of 13 to an average of 7 per 24 h and improved the patient's quality of life. The fluid and electrolyte balances normalized. The effect was sustained during follow-up for 6 mo with treatment at a daily dosage of 25 mg. The diarrhea worsened shortly after cessation of obeticholic acid. This case report supports the initial report that obeticholic acid may reduce bile acid production and improve symptoms in patients with bile acid diarrhea.
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8.
Importance of microbial defence systems to bile salts and mechanisms of serum cholesterol reduction.
Horáčková, Š, Plocková, M, Demnerová, K
Biotechnology advances. 2018;(3):682-690
Abstract
An important feature of the intestinal microbiota, particularly in the case of administered probiotic microorganisms, is their resistance to conditions in the gastrointestinal tract, particularly tolerance to and growth in the presence of bile salts. Bacteria can use several defence mechanisms against bile, including special transport mechanisms, the synthesis of various types of surface proteins and fatty acids or the production of exopolysaccharides. The ability to enzymatically hydrolyse bile salts occurs in a variety of bacteria. Choloylglycine hydrolase (EC 3.5.1.24), a bile salt hydrolase, is a constitutive intracellular enzyme responsible for the hydrolysis of an amide bond between glycine or taurine and the steroid nucleus of bile acids. Its presence was demonstrated in specific microorganisms from several bacterial genera (Lactobacillus spp., Bifidobacterium spp., Clostridium spp., Bacteroides spp.). Occurrence and gene arrangement encoding this enzyme are highly variable in probiotic microorganisms. Bile salt hydrolase activity may provide the possibility to use the released amino acids by bacteria as sources of carbon and nitrogen, to facilitate detoxification of bile or to support the incorporation of cholesterol into the cell wall. Deconjugation of bile salts may be directly related to a lowering of serum cholesterol levels, from which conjugated bile salts are synthesized de novo. Furthermore, the ability of microorganisms to assimilate or to bind ingested cholesterol to the cell wall or to eliminate it by co-precipitation with released cholic acid was also documented. Some intestinal microflora produce cholesterol reductase that catalyses the conversion of cholesterol to insoluble coprostanol, which is subsequently excreted in faeces, thereby also reducing the amount of exogenous cholesterol.
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9.
Cholesterol Transport Revisited: A New Turbo Mechanism to Drive Cholesterol Excretion.
de Boer, JF, Kuipers, F, Groen, AK
Trends in endocrinology and metabolism: TEM. 2018;(2):123-133
Abstract
A fine-tuned balance between cholesterol uptake and excretion by the body is pivotal to maintain health and to remain free from the deleterious consequences of cholesterol accumulation such as cardiovascular disease. The pathways involved in intracellular and extracellular cholesterol transport are a subject of intense investigation and are being unraveled in increasing detail. In addition, insight into the complex interactions between cholesterol and bile acid metabolism has increased considerably in the last couple of years. This review provides an overview of the mechanisms involved in cholesterol uptake and excretion, with a particular emphasis on the most recent progress in this field. Special attention is given to the transintestinal cholesterol excretion (TICE) pathway, which was recently demonstrated to have a remarkably high transport capacity and to be sensitive to pharmacological modulation.
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10.
Role of Bile Acids and the Biliary HCO3- Umbrella in the Pathogenesis of Primary Biliary Cholangitis.
van Niekerk, J, Kersten, R, Beuers, U
Clinics in liver disease. 2018;(3):457-479
Abstract
The biliary HCO3- umbrella hypothesis states that human cholangiocytes and hepatocytes create a protective apical alkaline barrier against millimolar concentrations of potentially toxic glycine-conjugated bile salts in bile by secreting HCO3- into the bile duct lumen. This alkaline barrier may retain biliary bile salts in their polar, deprotonated, and membrane-impermeant state to avoid uncontrolled invasion of apolar toxic bile acids, which initiate apoptosis, autophagy and senescence. In primary biliary cholangitis, defects of the biliary HCO3- umbrella, leading to impaired biliary HCO3- secretion have been identified. Current medical therapies stabilize the putatively defective biliary HCO3- umbrella and improve long-term prognosis.