Maralixibat (LIVMARLI) para el síndrome de Alagille / Maralixibat (LIVMARLI) for Alagille syndrome

INTRODUÇÃO: El síndrome de Alagille es una enfermedad autosómica dominante con expresión variable ocasionada por defectos en la vía de señalización del receptor Notch debido a mutaciones en los genes JAGGED1 (95%) y NOTCH2 (2,5%). Se encuentra clasificada, y reconocida por el Ministerio de Salud de la Nación, como una enfermedad poco frecuente con una incidencia de aproximadamente 1 cada 30.000 recién nacidos vivos.1­3 Es considerada una enfermedad multisistémica cuyas principales manifestaciones son colestasis crónica, enfermedad cardíaca congénita, embriotoxón posterior, fenotipo facial característico y vértebras en alas de mariposa. Si bien las manifestaciones clínicas son muy variables, la predominante es la colestasis crónica neonata, donde habitualmente co-existen en diferentes grados de severidad: hepatoesplenomegalia, hiperbilirrubinemia conjugada, hipercolesterolemia, hipertrigliceridemia, y concentraciones elevadas de ácidos biliares y enzimas hepáticas. La colestasis suele intensificarse hasta la edad escolar y luego, en algunos niños, mejora o permanece estable. 2 Además, suelen presentar retraso del crecimiento, prurito y xantomas. El prurito se halla entre los más graves debidos a afecciones hepáticas, suele ser invalidante y se presenta a partir del segundo semestre de vida. 4 La evolución hacia una enfermedad hepática progresiva, cirrosis y fallo hepático, con indicación de trasplante hepático, acontece en el 21 a 31% de los casos. En niños menores de cinco años pueden considerarse como predictores de enfermedad hepática sostenida y grave, la presencia de concentraciones mayores de bilirrubina total de 6,5mg/dL, bilirrubina conjugada 4,5 mg/dl y colesterol 520 mg/dl. OBJETIVO: El objetivo del presente informe es evaluar rápidamente los parámetros de eficacia, seguridad, costos y recomendaciones disponibles acerca del empleo de maralixibat para el tratamiento de personas con síndrome de Alagille. MÉTODOS: Se realizó una búsqueda bibliográfica en las principales bases de datos tales como PUBMED, LILACS, BRISA, COCHRANE, SCIELO, EMBASE, TRIPDATABASE como así también en sociedades científicas, agencias reguladoras, financiadores de salud y agencias de evaluación de tecnologías sanitarias. Se priorizó la inclusión de revisiones sistemáticas, ensayos clínicos controlados aleatorizados, evaluación de tecnología sanitaria y guías de práctica clínica de alta calidad metodológica. En PubMed se utilizó la estrategia de búsqueda que se detalla en el Anexo I. La fecha de búsqueda de información fue hasta el 16 de enero de 2023. Para la búsqueda en Pubmed se utilizó la siguiente estrategia de búsqueda: (maralixibat [Supplementary Concept] OR maralixibat [tiab] OR livmarli [tiab]) AND ("Alagille Syndrome" [MESH] OR "Alagille Syndrome" [tiab] OR Arteriohepatic Dysplasia [tiab]). RECOMENDACIONES: No se hallaron recomendaciones referentes al uso de maralixibat en la indicación especificada por parte de las Sociedades Científicas y Agencias de evaluación de tecnologías sanitarias en Argentina y nivel mundial. Actualmente el Instituto Nacional de Salud y Cuidados de Excelencia del Reino Unido (NICE, su sigla del inglés National Institute for Health and Care Excellence) del Reino Unido se encuentra evaluándolo. CONCLUSIONES: La evidencia que sustenta la aprobación de comercialización de maralixibat para el tratamiento del prurito colestásico en personas mayores a 2 meses de edad con síndrome de Alagille, por parte de las agencias regulatorias relevadas, se basa en un ensayo clínico aleatorizado con un diseño de retirada y con un bajo número de pacientes. Este estudio mostraría que la utilización de este fármaco podría mejorar al mediano plazo, el prurito, los niveles de colesterol, de ácidos biliares y mejorar la calidad de vida reportada por los cuidadores respecto al estado basal. Otros estudios sostendrían que esos beneficios se podrían mantener al largo plazo. Si bien al mediano plazo no se observarían interrupciones del tratamiento debido a eventos adversos graves, al largo plazo se ha descripto interrupciones principalmente debido a la aparición de hipertransaminasemia. Su comercialización se encuentra recientemente autorizada en Estados Unidos y Europa para el tratamiento del prurito colestásico en personas mayores a 2 meses de edad con síndrome de Alagille. Las agencias han otorgado la designación de medicamento huérfano y han advertido sobre la estrecha monitorización del hígado, mediante exámenes de laboratorio hepáticos y de vitaminas liposolubles. No se hallaron guías de práctica clínica actualizadas en Argentina y en el Mundo que mencionen la tecnología en la indicación evaluada. No se hallaron evaluaciones económicas publicadas, aunque el costo mensual medio estimado al precio de adquisición de referencia es excesivamente elevado (USD 67.760).

Alerta monitoramento do horizonte tecnológico: Odevixibat para o tratamento de colestase intra-hepática familiar progressiva / Technological horizon monitoring alert: Odevixibat for the treatment of progressive familial intrahepatic cholestasis

A TECNOLOGIA: Descrição da tecnologia: Odevixibat (Bylvay®) é uma pequena molécula, inibidora seletiva e reversível do transportador de ácido biliar (AB) ileal (IBAT), que atua localmente no intestino (com exposição sistêmica mínima) interrompendo a circulação entero-hepática. Foi desenvolvida para o tratamento de doenças hepáticas colestáticas, incluindo a colestase intra-hepática familiar progressiva (CIFP), atresia biliar e síndrome de Alagille. O fármaco bloqueia a reabsorção intestinal de AB, desviando-o para a excreção fecal, reduzindo o nível plasmático e a recaptação de AB no íleo distal, o que aumenta a sua depuração no cólon. Esse mecanismo de ação leva à diminuição ou desaparecimento do acúmulo sérico de AB, . tratando os sinais e sintomas associados, como a icterícia, o prurido, o retardo de crescimento e, consequentemente, os danos ao tecido hepático. Clinicamente, essa ação se reflete no retardo ou bloqueio da progressão da doença para insuficiência orgânica, evitando-se tratamentos invasivos como a cirurgia de diversão biliar e o transplante hepático. Condição clínica: A colestase intra-hepática familiar progressiva (CIFP) compõe um grupo heterogêneo de doenças genéticas autossômicas recessivas raras, caracterizadas por colestase hepatocelular. A CIFP é causada por defeito na síntese e transporte/secreção biliar. As manifestações clínicas da doença variam de leve a grave, com prurido, icterícia, acolia fecal, diarreia pela má absorção de lipídeos, hipovitaminoses e déficit de outros nutrientes, litíase biliar, hepatomegalia, esplenomegalia, hipertensão portal entre outros4 . Geralmente se apresenta na forma de doença grave de início precoce ainda na infância4,5 . A doença é caracterizada por início precoce de colestase, progredindo rapidamente para insuficiência hepática e normalmente requerendo transplante de fígado. Tem um impacto devastador na vida das crianças, bem como de seus pais e familiares. Sem cirurgia ou transplante de fígado (TH), apenas 50% dos pacientes com a CIFP sobrevivem até os 10 anos e quase nenhum até 20 anos de idade. INFORMAÇÕES REGULATÓRIAS: Informações sobre registro: Não foi localizado o registro do medicamento na Agência Nacional de Vigilância Sanitária (Anvisa). Nas agências U. S. Food and Drug Administration (FDA) e European Medicine Agency (EMA), o medicamento obteve registro para a indicação com a aprovação acelerada em 20 de julho de 2021 (NDA: 215498)20 e 16 e julho de 2021 (EMEA/H/C/004691)2 , respectivamente.. PANORAMA DE DESENVOLVIMENTO: Estratégia de busca: Foi realizada busca na base de dados "ClinicalTrials.gov" em 16 de março de 2022, usando termos referentes à doença e à tecnologia. Foram incluídos estudos de intervenção, de fase 3 e 4 com pacientes com colestase intra-hepática familiar progressiva. De forma complementar também foram buscadas informações sobre a tecnologia na literatura cinzenta. CONSIDERAÇÕES FINAIS: A colestase intra-hepática familiar progressiva (CIFP) é uma condição rara e grave, geralmente de evolução rápida, podendo progredir para insuficiência hepática, demandando desde cuidados de suporte nutricional, controle do prurido [sintoma que responde mal aos medicamentos (todos off-label) atualmente disponíveis], até transplante hepático. A doença acomete precocemente crianças e adultos jovens e interfere drasticamente no crescimento, desenvolvimento e na qualidade de vida desses pacientes e de seus familiares. Na fisiopatologia da CIFP, o nível sérico de sais biliares é um parâmetro importante na evolução para fibrose hepática e progressão para insuficiência orgânica, além de estar diretamente envolvido no desencadeamento do prurido, considerado um sintoma debilitante e que, para seu tratamento efetivo, exige procedimento invasivo, inicialmente como derivação biliar ou transplante hepático. Desse modo, o odevixibat surge como opção de tratamento para atender à essa demanda. As principais evidências favoráveis ao uso do odevixibat para o tratamento da CIFP, inclusive foram usadas para embasar a aprovação pelo NICE21 , vem de um ensaio clínico randomizado de fase 3 concluído, o PEDFIC124, e de um estudo de extensão aberto de braço único em andamento o PEDFIC223 , ambos incluídos na presente análise. Ambos os estudos incluíram pessoas com diagnóstico clínico de CIFP 1 ou 2, sendo que o odevixibat foi eficaz na redução do nível sérico de ácidos biliares e prurido em um percentual significativo de pacientes em comparação ao placebo, bem como melhora significativa na qualidade de vida relacionada à saúde e no número de pessoas submetidas a cirurgias de derivação biliar ou transplantes de fígado. Em estudo publicado por Baumann U. et al 25, os resultados em pacientes com colestase sintomática que receberam odevixibat em doses diferentes, foram bastante favoráveis em comparação à linha de base, em todos os desfechos avaliados, incluindo a segurança. O mecanismo de ação do odevixibat requer que a circulação enterohepática de ácidos biliares e o transporte de sais biliares para os canalículos biliares sejam preservados. Condições, medicamentos ou procedimentos cirúrgicos que prejudiquem a motilidade gastrointestinal ou a circulação enterohepática de ácidos biliares, incluindo o transporte de sais biliares para os canalículos biliares, têm o potencial de reduzir a eficácia do odevixibat. Por esse motivo, pacientes com CIFP 2 que apresentam ausência completa ou ausência de função da proteína da bomba de exportação de sal biliar (BSEP) (ou seja, pacientes com subtipo BSEP3 de CIFP2) podem não responder ao odevixibat. Existem dados clínicos limitados ou inexistentes com odevixibat em subtipos de CIFP diferentes de 1 e 2. Odevixibat pode não ser eficaz em pacientes com CIFP tipo 2 com variantes ABCB11, resultando em ausência completa ou não funcional da proteína da bomba de exportação de sais biliares (BSEP-3). É importante salientar que nos estudos aqui apresentados, não houve comparação direta do odevixibat com tratamento usual para CIFP, como medicamentos empregados rotineiramente para prurido na doença, nem com qualquer intervenção cirúrgica, como derivação biliar para o alívio da colestase ou transplante hepático. Outro ponto a ser destacado é que indicação aprovada tanto nos EUA como na UE não se renstringem aos tipos 1 e 2 da doença, entretanto os estudos clínicos realizados até o momento foram para apenas com pacientes portadores desses tipos. Além disso, para que ocorra a oferta desse medicamento no SUS, é necessária sua análise pela Conitec, conforme disposto na Lei nº 12.401/2011, que alterou a Lei nº 8.080/1990. Os relatórios de recomendação da Conitec levam em consideração as evidências científicas sobre eficácia, a acurácia, a efetividade e a segurança do medicamento, e, também, a avaliação econômica comparativa dos benefícios e dos custos em relação às tecnologias já incorporadas e o impacto da incorporação da tecnologia no SUS.

Odevixibat para prurito debido a colestasis intrahepática familiar progresiva / Odevixibat for pruritus due to cholestasis progressive familial intrahepatic

INTRODUCCIÓN: Las condiciones que causan hiperbilirrubinemia pueden clasificarse en aquellas que resultan en una hiperbilirrubinemia predominantemente no conjugada, y aquellas que están asociadas con una elevación de las formas conjugadas y no conjugadas de bilirrubina. La eliminación de la bilirrubina conjugada en la bilis se ve afectada en varios trastornos hereditarios a través de diferentes mecanismos, aunque en todas estas situaciones se comparte con el defecto excretor de todos o algunos otros aniones orgánicos. Entre los genes que sus mutaciones usualmente conllevan a síndromes hereditarios de colestasis intrahepática se encuentran el SERPINAI (alfa 1-antitripsina), JAG1 (que causa el síndrome de Alagille), ATP8B1 (también conocido como FIC1), ABCB11 (bomba de exportación de sales biliares [BSEP]), MDR3 (ABCB4) y MRP2 (que causa el síndrome de Dubin-Johnson); mientras que no se ha identificado el gen del síndrome de Rotor. Otras enfermedades hereditarias, como la colestasis intrahepática familiar progresiva y la colestasis intrahepática recurrente benigna, provocan hiperbilirrubinemia conjugada como consecuencia de la reducción del flujo biliar. La colestasis intrahepática familiar progresiva es un grupo heterogéneo de trastornos, caracterizado por una secreción defectuosa de ácidos biliares u otros componentes de la bilis. Se clasifica en cuatro tipos según la mutación genética predominante identificada; donde el tipo I es conocida como enfermedad de Byler o colestasis familiar de Groenlandia, la tipo II se asemeja clínicamente a la enfermedad de Byler, pero ocurre principalmente en Oriente Medio y Europa, la tipo III que involucra el gen ABCB4 (también conocido como proteína 3 Pglicoproteína de resistencia a múltiples fármacos) y tipo IV que es una enfermedad hepática colestásica crónica grave. TECNOLOGÍA: Odevixibat es un inhibidor no absorbible del transportador de ácidos biliares ileal reversible, que disminuye la reabsorción de ácidos biliares (principalmente formas de sal) del íleon terminal. Se desconoce el mecanismo exacto por el cual odevixibat mejora el prurito en pacientes con colestasis intrahepática familiar progresiva, pero puede implicar la inhibición de del transportador de ácidos biliares ileal reversible. Se administra una vez por día por vía oral a 40 mcg/kg/día, donde según la respuesta clínica a los tres meses puede a incrementarse en 40 mcg/kg/día hasta 120 mcg/kg/día. Cuando se lo coadministra con colestiramina debe tomarse al menos con cuatro horas de diferencia entre fármacos, y también interacciona con la absorción de vitaminas liposolubles. Las formulaciones disponibles son en cápsula para espolvorear de 200 mcg y 600 mcg, y cápsulas de 400 mcg y 1200 mcg. Entre los eventos adversos graves más frecuentemente identificados se destacan la deficiencia de vitamina, dolor abdominal, diarrea persistente, esplenomegalia e incremento de las enzimas hepáticas. OBJETIVO: El objetivo del presente informe es evaluar rápidamente los parámetros de eficacia, seguridad, costos y recomendaciones disponibles acerca del empleo de odevixibat para el tratamiento del prurito debido a colestasis intrahepática familiar progresiva. MÉTODOS: Se realizó una búsqueda bibliográfica en las principales bases de datos tales como PUBMED, LILACS, BRISA, COCHRANE, SCIELO, EMBASE, TRIPDATABASE como así también en sociedades científicas, agencias reguladoras, financiadores de salud y agencias de evaluación de tecnologías sanitarias. Se priorizó la inclusión de revisiones sistemáticas, ensayos clínicos controlados aleatorizados, evaluación de tecnología sanitaria y guías de práctica clínica de alta calidad metodológica. CONCLUSIONES: No se hallaron ensayos clínicos aleatorizados publicados con revisión de pares que hayan evaluado la eficacia y seguridad de odevixibat para el tratamiento del prurito debido a colestasis intrahepática familiar progresiva. Las agencias regulatorias de Estados Unidos y Europa han autorizado su comercialización en la indicación evaluada de forma acelerada, a la espera de ensayos clínicos confirmatorios, brindando la designación de medicamento huérfano. El tratamiento consistente en odevixibat es de alto costo para Argentina. No se hallaron recomendaciones actualizadas en Argentina y en el Mundo que mencionen la tecnología en la indicación evaluada.

A pharmacokinetics-pharmacodynamics study of single-dose total glucosides of paeony capsule on reducing serum total bile acid in hepatic injury rats.

CONTEXT: Total Glucosides of Paeony (TGP) capsule possesses various hepatoprotective activities. No study is available concerning TGP's concentration-effect relationship on hepatoprotection. OBJECTIVE: To establish a pharmacokinetics-pharmacodynamics (PK-PD) modelling on TGP capsule's hepatoprotection after a single oral administration in hepatic injury rats. MATERIALS AND METHODS: Male Sprague-Dawley rats were divided into five groups (n = 6): control, model (hepatic injury), treated-H (2.82 g/kg), treated-M (1.41 g/kg), and treated-L (0.705 g/kg) groups. All treated groups rats were intragastrically administered a single dose. An LC-MS/MS method was applied to determine paeoniflorin (Pae) and albiflorin (Alb) in rat serum. The effects of single-dose TGP on serum alanine transaminase (ALT), aspartate transaminase (AST) and total bile acid (TBA) were evaluated in hepatic injury rats. RESULTS: Single dose (2.82, 1.41, or 0.705 g/kg) TGP capsule could real-time down-regulate serum TBA but not ALT and AST in hepatic injury rats within 20 h. An inhibitory effect Sigmoid Emax of PK-PD modelling was established using Pae and Alb as PK markers and serum TBA as effect index. Pharmacodynamic parameters were calculated. For treated-H, treated-M and treated-L group, respectively, E0 were 158.1, 226.9 and 245.4 µmol/L for Pae, 146.1, 92.9 and 138.4 µmol/L for Alb, Emax were 53.0, 66.0, and 97.1 µmol/L for Pae, 117.4, 249.7 and 60.0 µmol/L for Alb, and EC50 were 9.3, 5.2 and 2.7 µg/mL for Pae, 2.3, 0.8, and 0.8 µg/mL for Alb. DISCUSSION AND CONCLUSIONS: Serum TBA is a sensitive effect index for TGP's single dose PK-PD modelling, and it is potential for further multi-dose studies of TGP' effect on hepatic injury. The study provides valuable information for TGP's mechanistic research and rational clinical application.

Identification of Triterpene Acids in Poria cocos Extract as Bile Acid Uptake Transporter Inhibitors.

Literature reports that Poria cocos reduces blood lipid levels; however, the underlying mechanism remains unclear. Blood lipid levels are closely related to the enterohepatic circulation of bile acids, where uptake transporters playing a significant role. P. cocos extract is commonly used in traditional prescriptions and food supplements in China. We investigated the effects of P. cocos and its five triterpene acids on bile acid uptake transporters, including intestinal apical sodium-dependent bile acid transporter (ASBT) and hepatic sodium/taurocholate cotransporting polypeptide (NTCP). Triterpene acids were fingerprinted by high-performance liquid chromatography-TripleTOF and quantified by ultraperformance liquid chromatography/tandem mass spectrometry. The inhibitory effect of P. cocos and its five major representative triterpene acids on ASBT and NTCP was investigated by in vitro assays using Xenopus oocytes expressing ASBT and NTCP. P. cocos extract exhibited significant inhibitory effects with half-maximum inhibition constants of 5.89 µg/ml and 14.6 µg/ml for NTCP and ASBT, respectively. Among five triterpene acids, poricoic acid A, poricoic acid B, and polyporenic acid C significantly inhibited NTCP function. Poricoic acid A, poricoic acid B, and dehydrotumulosic acid significantly inhibited ASBT function. The representative triterpene acid, poricoic acid A, was identified as a competitive inhibitor of NTCP with an inhibitory constant of 63.4 ± 18.7 µM. In conclusion, our results indicate that both P. cocos extract and its major triterpenes are competitive inhibitors of ASBT and NTCP. Accordingly, it was suggested that competitive inhibition of these bile acid transporters is one of the underlying mechanisms for the hypolipidemic effect of P. cocos. SIGNIFICANCE STATEMENT: Poria cocos, a commonly used Chinese herbal medicine and food supplement, demonstrates significantly inhibitory effects on the function of apical sodium-dependent bile acid transporter and sodium/taurocholate cotransporting polypeptide. P. cocos has potential to reduce the blood lipid through inhibition of these uptake transporters in enterohepatic circulation of bile acid.

Low-density lipoprotein cholesterol lowering treatment: the current approach.

In the last 50 years, several clinical and epidemiological studies during have shown that increased levels of low-density lipoprotein cholesterol (LDLc) are associated with the development and progression of atherosclerotic lesions. The discovery of ß-Hydroxy ß-methylglutaryl-CoA reductase inhibitors (statins), that possess LDLc-lowering effects, lead to a true revolution in the prevention and treatment of cardiovascular diseases. Statins remain the cornerstone of LDLc-lowering therapy. Lipid-lowering drugs, such as ezetimibe and bile acid sequestrants, are prescribed either in combination with statins or in monotherapy (in the setting of statin intolerance or contraindications to statins). Microsomal triglyceride transfer protein inhibitors and protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are other drug classes which have been investigated for their potential to decrease LDLc. PCSK9 have been approved for the treatment of hypercholesterolemia and for the secondary prevention of cardiovascular events. The present narrative review discusses the latest (2019) guidelines of the European Atherosclerosis Society/European Society of Cardiology for the management of dyslipidemia, focusing on LDLc-lowering drugs that are either already available on the market or under development. We also consider "whom, when and how" do we treat in terms of LDLc reduction in the daily clinical practice.

Interactions between Atorvastatin and the Farnesoid X Receptor Impair Insulinotropic Effects of Bile Acids and Modulate Diabetogenic Risk.

Bile acids such as chenodeoxycholic acid (CDC) acutely enhance insulin secretion via the farnesoid X receptor (FXR). Statins, which are frequently prescribed for patients with type 2 diabetes who suffer from dyslipidemia, are known for their diabetogenic risk and are reported to interact with the FXR. Our study investigates whether this interaction is relevant for beta cell signaling and plays a role for negative effects of statins on glycemic control. Experiments were performed with islets and islet cells from C57BL/6N wild-type and FXR-knockout (KO) mice. Culturing islets with atorvastatin (15 µM) for 24 hours decreased glucose-stimulated insulin secretion by approximately 30% without affecting ATP synthesis. Prolonged exposure for 7 days lowered the concentration necessary for impairment of insulin release to 150 nM. After 24-hour culture with atorvastatin, the ability of CDC (500 nM) to elevate [Ca2+]c was diminished and the potentiating effect on insulin secretion was completely lost. Mevalonate largely reduced the negative effect of atorvastatin. Nuclear activity of FXR was reduced by atorvastatin in a mouse FXR reporter assay. The atorvastatin-induced decrease in insulin release was also present in FXR-KO mice. Although not a prerequisite, FXR seems to influence the degree of damage caused by atorvastatin depending on its interaction with CDC: Preparations responding to CDC with an increase in insulin secretion under control conditions were less impaired by atorvastatin than preparations that were nonresponsive to CDC. Extended stimulation of FXR by the synthetic agonist GW4064, which is suggested to induce translocation of FXR from the cytosol into the nucleus, increased the inhibitory effect of atorvastatin. In conclusion, atorvastatin inhibits insulin release and prevents positive effects of bile acids on beta cell function. Both interactions may contribute to progression of type 2 diabetes mellitus. SIGNIFICANCE STATEMENT: This study shows that the diabetogenic risk of statins is coupled to the activity of farnesoid X receptor (FXR)-dependent signaling pathways in beta cells. On the one hand, statins abolish the insulinotropic effects of bile acids and on the other hand, FXR determines the level of impairment of islet function by the statin.

Molecular Insights into the Mechanisms Underlying the Cholesterol- Lowering Effects of Phytosterols.

Dietary phytosterols, which comprise plant sterols and stanols, reduce plasma Low-Density Lipoprotein-Cholesterol (LDL-C) levels when given 2 g/day. Since this dose has not been reported to cause health-related side effects in long-term human studies, food products containing these plant compounds are used as potential therapeutic dietary options to reduce LDL-C and cardiovascular disease risk. Several mechanisms have been proposed to explain the cholesterol-lowering action of phytosterols. They may compete with dietary and biliary cholesterol for micellar solubilization in the intestinal lumen, impairing intestinal cholesterol absorption. Recent evidence indicates that phytosterols may also regulate other pathways. Impaired intestinal cholesterol absorption is usually associated with reduced cholesterol transport to the liver, which may reduce the incorporation of cholesterol into Very-Low- Density Lipoprotein (VLDL) particles, thereby lowering the rate of VLDL assembly and secretion. Impaired liver VLDL production may reduce the rate of LDL production. On the other hand, significant evidence supports a role for plant sterols in the Transintestinal Cholesterol Excretion (TICE) pathway, although the exact mechanisms by which they promote the flow of cholesterol from the blood to enterocytes and the intestinal lumen remains unknown. Dietary phytosterols may also alter the conversion of bile acids into secondary bile acids, and may lower the bile acid hydrophobic/hydrophilic ratio, thereby reducing intestinal cholesterol absorption. This article reviews the progress to date in research on the molecular mechanisms underlying the cholesterol-lowering effects of phytosterols.

The protective effect and mechanism of the FXR agonist obeticholic acid via targeting gut microbiota in non-alcoholic fatty liver disease.

Background: It is reported that various diseases such as non-alcoholic fatty liver disease (NAFLD) are associated with imbalance of microbiome. And FXR has been well investigated in liver diseases. Purpose: The objective of this study was to identify the role of farnesoid X receptor agonist obeticholic acid via targeting gut microbiota in NAFLD. Patients and methods: Male C57BL/6 mice were fed either a normal-chow diet or a high-fat diet (HFD). Obeticholic acid(30mg/(kg·d)) and/or a combination of antibiotics were administered orally by gavage to mice for 12 weeks. Gut microbiota profiles were established through 16S rRNA amplicon sequencing. The effects of obeticholic acid on liver inflammation, the gut barrier, endotoxemia, gut microbiome and composition of the bile acid were also investigated. Results: Obeticholic acid treatment can significantly improve obesity, circulation metabolism disorders, liver inflammation and fibrosis, and intestinal barrier damage caused by HFD. Removal of normal commensal bacteria can weaken the effect of obeticholic acid. The gut microbial structure was changed, and abundance of Blautia was increased significantly after treated with obeticholic acid. After obeticholic acid treatment, the concentration of taurine-bound bile acid caused by HFD was reduced in the liver. Conclusion: Taken together, these data suggest that obeticholic acid has aprotective effect on NAFLD via changing the components of gut microbiota, specifically increasing the abundance of Blautia.

NRF2 antioxidant response protects against acidic bile salts-induced oxidative stress and DNA damage in esophageal cells.

Gastroesophageal reflux disease (GERD) is the main risk factor for Barrett's tumorigenesis. In this study, we investigated the role of NRF2 in response to exposure to acidic bile salts (ABS), in conditions that mimic GERD, using Barrett's esophagus cell models. We detected an increase in NRF2 protein levels, following exposure to ABS. We found oxidization of cysteines (cysteines with oxidized thiol groups) in KEAP1 protein with a weaker interaction between NRF2 and KEAP1, following ABS exposure. Treatment with bile salts increased nuclear NRF2 levels, enhancing its transcription activity, as measured by an ARE (antioxidant response element) luciferase reporter assay. The mRNA expression levels of NRF2 target genes, HO-1 and GR, were increased in response to ABS exposure. Using genetic overexpression and knockdown of NRF2, we found that NRF2 has a critical role in suppressing ABS-induced ROS levels, oxidative DNA damage, DNA double strand breaks, and apoptosis. Collectively, our results suggest that transient induction of NRF2 in response to ABS plays a pivotal role in protecting esophageal cells by maintaining the levels of oxidative stress and DNA damage below lethal levels under GERD conditions.

Update on the management of chronic idiopathic constipation.

Chronic idiopathic constipation is a functional bowel disorder characterized by difficult, infrequent, and/or incomplete defecation, affecting 35 million adult Americans, resulting in more than millions of physician visits annually. Symptoms of constipation vary from patient to patient and impact all age groups and patient populations in the United States. The definition of constipation was previously not well specified, beyond stool frequency, and has been revised to incorporate the patient perspective and experience in addition to specific criteria created by the Rome Foundation. In the absence of red-flag (alarm) symptoms, and with a normal physical (including rectal) examination, patients can initially be empirically treated for their symptoms of chronic constipation assuming adequate follow-up is arranged. Unfortunately, both patients and healthcare providers have documented unmet needs with currently available therapeutic options, thus prompting research for new agents with novel mechanisms of action that are both efficacious and safe.

Bile acids elicited endothelium-dependent vasoconstrictor hypo-activity through TRPV4 channels in the thoracic aorta of bile duct ligation rats.

Numerous studies have demonstrated the impaired cardiovascular reactivity in cholestasis patients and bile duct ligated animals. However, the underlying mechanism remains uncertain. Transient receptor potential cation V4 (TRPV4) channels are reported to be naturally expressed in the cardiovascular system, especially on endothelial cells. However, the role of TRPV4 (transient receptor potential vanilloid 4) in regulating vascular reactivity is poorly established. In this study, we first determined that bile acids elicited endothelium-dependent vasoconstrictor hypo-activity via TRPV4 channels, which further activated cyclooxygenase 2 (COX2). Myography results demonstrated that the vascular contractile response was attenuated in BDL rats when exposed to 60 mmol/L KCl. Real time PCR and western blotting results showed that bile duct ligation (BDL) induced a time-dependent increase in TRPV4 expression levels. In addition, bile acids upregulated the expression of TRPV4 protein, which proved to be located on the cell surface of endothelial cells, and induced intracellular Ca2+ events. The relaxation response was increased while the contractile response was decreased in BDL rats, and those effects were reversed by a TRPV4 inhibitor (HC067047). Contractions induced by norepinephrine were primarily inhibited by the COX2 inhibitor, but not the NOS inhibitor, and the expression of COX2 was downregulated after TRPV4 inhibition. These data indicated that TRPV4/COX2 pathways in the endothelium are involved in vasoconstrictor hypo-activity. Our current results suggested that the TRPV4 pathway is involved in the regulation of bile acids in vasoconstrictor hypo-activity in bile duct ligation rats.

Suppression of Hepatic Bile Acid Synthesis by a non-tumorigenic FGF19 analogue Protects Mice from Fibrosis and Hepatocarcinogenesis.

Critical regulation of bile acid (BA) pool size and composition occurs via an intensive molecular crosstalk between the liver and gut, orchestrated by the combined actions of the nuclear Farnesoid X receptor (FXR) and the enterokine fibroblast growth factor 19 (FGF19) with the final aim of reducing hepatic BA synthesis in a negative feedback fashion. Disruption of BA homeostasis with increased hepatic BA toxic levels leads to higher incidence of hepatocellular carcinoma (HCC). While native FGF19 has anti-cholestatic and anti-fibrotic activity in the liver, it retains peculiar pro-tumorigenic actions. Thus, novel analogues have been generated to avoid tumorigenic capacity and maintain BA metabolic action. Here, using BA related Abcb4-/- and Fxr-/- mouse models of spontaneous hepatic fibrosis and HCC, we explored the role of a novel engineered variant of FGF19 protein, called FGF19-M52, which fully retains BA regulatory activity but is devoid of the pro-tumoral activity. Expression of the BA synthesis rate-limiting enzyme Cyp7a1 is reduced in FGF19-M52-treated mice compared to the GFP-treated control group with consequent reduction of BA pool and hepatic concentration. Treatment with the non-tumorigenic FGF19-M52 strongly protects Abcb4-/- and Fxr-/- mice from spontaneous hepatic fibrosis, cellular proliferation and HCC formation in terms of tumor number and size, with significant reduction of biochemical parameters of liver damage and reduced expression of several genes driving the proliferative and inflammatory hepatic scenario. Our data bona fide suggest the therapeutic potential of targeting the FXR-FGF19 axis to reduce hepatic BA synthesis in the control of BA-associated risk of fibrosis and hepatocarcinoma development.

Curcumin prevents the bile reflux-induced NF-κB-related mRNA oncogenic phenotype, in human hypopharyngeal cells.

The presence of bile is not an uncommon finding in acidic oesophageal and extra-oesophageal refluxate, possibly affecting the hypopharyngeal mucosa and leading to neoplastic events. We recently demonstrated that acidic bile (pH ≤ 4.0) can induce NF-κB activation and oncogenic mRNA phenotype in normal hypopharyngeal cells and generate premalignant changes in treated hypopharyngeal mucosa. We hypothesize that curcumin, a dietary inhibitor of NF-κB, may effectively inhibit the acidic bile-induced cancer-related mRNA phenotype, in treated human hypopharyngeal primary cells (HHPC), supporting its potential preventive use in vivo. Luciferase assay, immunofluorescence, Western blot, qPCR and PCR microarray analysis were used to explore the effect of curcumin in HHPC exposed to bile (400 µmol/L) at acidic and neutral pH. Curcumin successfully inhibited the acidic bile-induced NF-κB signalling pathway (25% of analysed genes), and overexpression of NF-κB transcriptional factors, c-REL, RELA(p65), anti-apoptotic bcl-2, oncogenic TNF-α, EGFR, STAT3, WNT5A, ΔNp63 and cancer-related IL-6. Curcumin effectively reduced bile-induced bcl-2 overexpression at both acidic and neutral pH. Our novel findings suggest that, similar to pharmacologic NF-κB inhibitor, BAY 11-7082, curcumin can suppress acidic bile-induced oncogenic mRNA phenotype in hypopharyngeal cells, encouraging its future in vivo pre-clinical and clinical explorations in prevention of bile reflux-related pre-neoplastic events mediated by NF-κB.

Targeted Metabolomics Reveals a Protective Role for Basal PPARα in Cholestasis Induced by α-Naphthylisothiocyanate.

α-Naphthylisothiocyanate (ANIT) is an experimental agent used to induce intrahepatic cholestasis. The Ppara-null mouse line is widely employed to explore the physiological and pathological roles of PPARα. However, little is known about how PPARα influences the hepatotoxicity of ANIT. In the present study, wild-type and Ppara-null mice were orally treated with ANIT to induce cholestasis. The serum metabolome of wild-type mice segregated from that of the Ppara-null mice, driven by changes of bile acid (BA) metabolites. Alkaline phosphatase and total BAs were elevated preferentially in Ppara-null mice, which correlated with changes in Cyp7a1, Cyp8b1, Mrp3, Cyp3a11, Cyp2b10, Ugt1a2, and Ugt1a5 genes and showed cross-talk between basal PPARα and potentially adaptive pathways. Il6, Tnfa, and target genes in the STAT3 pathway ( Socs3, Fga, Fgb, and Fgg) were up-regulated in Ppara-null mice but not in wild-type mice. The JNK pathway was activated in both mouse lines, while NF-κB and STAT3 were activated only in Ppara-null mice. These data suggest protection against cholestasis by basal PPARα involves regulation of BA metabolism and inhibition of NF-κB/STAT3 signaling. Considering studies on the protective effects of both basal and activated PPARα, caution should be exercised when one attempts to draw conclusions in which the PPARα is modified by genetic manipulation, fasting, or activation in pharmacological and toxicological studies.

Molecular aspects of hypercholesterolemia treatment: current perspectives and hopes.

Hypercholesterolemia is a pathological condition which has been reported in 39% of the worlds' adult population. We aimed to review molecular aspects of current and novel therapeutic approaches based on low-density lipoprotein cholesterol lowering strategies. Pathogenic mutations in the LDLR, ApoB, PCSK9 and LDLRAP genes cause deficient clearance of circulating low-density lipoprotein cholesterol particles via hepatic LDL receptor. This leads to increased plasma LDL cholesterol levels from birth, which can cause LDL depositions in the arterial walls. Ultimately, it progresses to atherosclerosis and an increased risk of premature cardiovascular diseases. Currently, statins, Ezetimibe, Bile acid sequestrants and PCSK9 inhibitors are the main therapeutic agents for the treatment of hypercholesterolemia. Moreover, novel RNA-based therapy had a strong impact on therapeutic strategies in recent decades. Additional development in understanding of the molecular basis of hypercholesterolemia will provide opportunities for the development of targeted therapy in the near future. Key Messages The most common genes involved in hypercholesterolemia are LDLR, PCSK9 and ApoB. Pharmacogenetic effects are typically constrained to pathways closely related to the pharmacodynamics and pharmacokinetics. Change in lifestyle and diet along with treatment of the underlying disease and drug therapy are the current therapeutic strategies.

The bile acid-sequestering resin sevelamer eliminates the acute GLP-1 stimulatory effect of endogenously released bile acids in patients with type 2 diabetes.

AIMS: Discovery of the specific bile acid receptors farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) in enteroendocrine L cells has prompted research focusing on the impact of bile acids on glucagon-like peptide-1 (GLP-1) secretion and glucose metabolism. The aim of the present study was to assess the GLP-1 secretory and gluco-metabolic effects of endogenously released bile, with and without concomitant administration of the bile acid-sequestering resin, sevelamer, in patients with type 2 diabetes. MATERIALS AND METHODS: We performed a randomized, placebo-controlled, double-blinded cross-over study including 15 metformin-treated patients with type 2 diabetes. During 4 experimental study days, either sevelamer 3200 mg or placebo in combination with intravenous infusion of cholecystokinin (CCK) (0.4 pmol sulfated CCK-8/kg/min) or saline was administered in randomized order. The primary endpoint was plasma GLP-1 excursions as measured by incremental area under the curve. Secondary endpoints included plasma responses of glucose, triglycerides, insulin, CCK, fibroblast growth factor-19 and 7α-hydroxy-4-cholesten-3-one (C4). In addition, gallbladder dynamics, gastric emptying, resting energy expenditure, appetite and ad libitum food intake were assessed. RESULTS: CCK-mediated gallbladder emptying was demonstrated to elicit a significant induction of GLP-1 secretion compared to saline, whereas concomitant single-dose administration of the bile acid sequestrant sevelamer was shown to eliminate the acute bile acid-induced increase in plasma GLP-1 excursions. CONCLUSIONS: Single-dose administration of sevelamer eliminated bile acid-mediated GLP-1 secretion in patients with type 2 diabetes, which could be explained by reduced bile acid stimulation of the basolaterally localized TGR5 on enteroendocrine L cells.

Bile acid sequestrants for glycemic control in patients with type 2 diabetes: A systematic review with meta-analysis of randomized controlled trials.

AIM: To evaluate the effects of bile acid sequestrants (BASs) versus placebo, no intervention or active comparators on glycemic control in type 2 diabetes. METHODS: Data were retrieved and a systematic review with meta-analyses was performed. We evaluated bias control and subgroup and sensitivity analyses were performed to evaluate heterogeneity and bias. RESULTS: We included 17 trials with a total of 2950 patients randomized to BASs (colesevelam or colestimide) versus placebo, no intervention, statins or sitagliptin. Random-effects meta-analysis showed that patients randomized to BASs had a lower hemoglobin A1c at the end of treatment compared with the control group (mean difference-0.55%; 95% confidence interval-0.64 to -0.46). Analysis of trials with low risk of bias in all domains confirmed the findings. Data on adverse events were limited. There were no differences between trials stratified by the control group and no evidence of publication bias or small study effects. CONCLUSIONS: Our analyses found that BAS treatment improves glycemic control. The size of the effect was clinically relevant and despite limited safety data, our findings support the inclusion of BASs in current diabetes management algorithms for type 2 diabetes.

An estrogen receptor ß-selective agonist inhibits non-alcoholic steatohepatitis in preclinical models by regulating bile acid and xenobiotic receptors.

Non-alcoholic steatohepatitis (NASH) affects 8-10 million people in the US and up to 75% of obese individuals. Despite this, there are no approved oral therapeutics to treat NASH and therefore the need for novel approaches exists. The estrogen receptor ß (ER-ß)-selective agonist, ß-LGND2, inhibits body weight and white adipose tissue, and increases metabolism, resulting in higher energy expenditure and thermogenesis. Due to favorable effects of ß-LGND2 on obesity, we hypothesized that ß-LGND2 will prevent NASH directly by reducing lipid accumulation in the liver or indirectly by favorably changing body composition. Male C57BL/6 mice fed with high fat diet (HFD) for 10 weeks or methionine choline-deficient diet for four weeks and treated with vehicle exhibited altered liver weights by twofold and increased serum transaminases by 2-6-folds. These changes were not observed in ß-LGND2-treated animals. Infiltration of inflammatory cells and collagen deposits, an indication of fibrosis, were observed in the liver of mice fed with HFD for 10 weeks, which were effectively blocked by ß-LGND2. Gene expression studies in the liver indicate that pregnane X receptor target genes were significantly increased by HFD, and the increase was inhibited by ß-LGND2. On the other hand, metabolomics indicate that bile acid metabolites were significantly increased by ß-LGND2. These studies demonstrate that an ER-ß agonist might provide therapeutic benefits in NASH by directly modulating the function of xenobiotic and bile acid receptors in the liver, which have important functions in the liver, and indirectly, as demonstrated before, by inhibiting adiposity. Impact statement Over 75-90% of those classified as clinically obese suffer from co-morbidities, the most common of which is non-alcoholic steatohepatitis (NASH). While there are currently no effective treatment approaches for NASH, data presented here provide preliminary evidence that an estrogen receptor ß-selective ligand could have the potential to reduce lipid accumulation and inflammation, and protect liver from NASH.