Efecto protector del factor de crecimiento de hepatocitos (HGF) en un modelo murino de colestasis

Cholestasis is a condition associated with a full or partial reduction in the bile flow that reaches the duodenum, caused either by a mechanical blockage impeding the normal flow of bile through the intra an d extrahepatic bile ducts (obstructive cholestasis) or due to alterations on the hepatocellular or ductular mechanisms of bile formation (functional cholestasis). Since it is an often a serious health condition with limited therapeutic options both in number and efficacy, it is necessary to carry out studies with potentially therapeutic molecules that could prevent or co unteract the damage generated by this pathology. Such is the case of hepatocyte growth factor (HGF), a growth factor with powerful antioxid ant, proliferative, anti - apoptotic and motility - stimulating effects, among others. To perform these effects, this growth factor requires activation of many transcription factors, including Nrf2, which regulates, through its target genes, the redox balance within the cell. Cholestasis is a condition associated with a full or partial reduction in the bile flow that reaches the duodenum, caused either by a mechanical blockage impeding the normal flow of bile through the intra - and extrahepatic bile ducts (obstructive cholestasis) or due to alterations on the hepatocellular or ductular mechanisms of bile formation (functional cholestasis). Since it is an often a serious health condition with limited therapeutic options both in number and efficacy, it is necessary to carry out studies with potentially therapeutic molecules that could prevent or co unteract the damage generated by this pathology. Such is the case of hepatocyte growth factor (HGF), a growth factor with powerful antioxid ant, proliferative, anti - apoptotic and motility - stimulating effects, among others. To perform these effects, this growth factor requires activation of many transcription factors, including Nrf2, which regulates, through its target genes, the redox balance within the cell. In this study, we evaluated the ant i - cholestasic capacity of HGF to counteract the damage caused by ANIT (a well-known model of cholestasis), and also the activation of Nrf2 as a putative key factor in the anti - cholesta t ic HGF effect. We o bserved that HGF has clear anti - cholestasic effects, because serum biochemical markers of liver integrity were improved, and liver histological ANIT injury decreased. This could be explained because this growth factor produced an enhancement in the express ion of basolateral and canalicular efflux transporters and of antioxidant enzymes induced by Nrf2. O ur results allow us to propose HGF as a highly efficient anti - cholestasic agent for the first time.La colestasis es un síndrome asociado a una reducción total o parcial del flujo biliar que llega al duodeno, producto de un bloqueo mecánico que impide su paso a través de las vías biliares intra o extrahepáticas (colestasis obstructiva) o a alteraciones hepatobiliares de los mecanismos hepatocelulares o ductulates de formación de bilis (colestasis funcional). Debido a su frecuente gravedad y las limitadas alternativas terapéuticas con que se cuenta, tanto en número como en eficacia, es necesario realizar estudios con moléculas potencialmente terapéuticas que permitan evitar o contrarrestar el daño ocasionado por esta patología. Tal es el caso del factor de crecimiento hepatocitos (HGF), el cual es un factor de crecimiento con potentes efectos antioxidantes, proliferativos, antiapoptóticos, y de motilidad, por mencionar algunos. Esto lo hace activando diversos factores de transcripción, como Nrf2, el cual regula el estado redox de la célula a través de sus genes blanco. En el presente estudio, se evaluó la capacidad anticolestásica de HGF ante el daño por ANIT (un conocido modelo de colestasis), y se indagó la activación de Nrf2 como un posible factor clave en los efectos anticolestásicos de HGF. Se observó que HGF tiene claros efectos anticolestásicos, ya que restableció los niveles séricos de las pruebas bioquímicas de integridad hepática e indujo una mejora en las lesiones histológicas hepáticas ocasionad as por ANIT. Esto s e de be a que el HGF produjo un aumento en la expresión de transportadores basolaterales y canaliculares de exportación y enzimas antioxidantes que son activadas por Nrf2. Nuestros resultados permiten proponer por primera vez a HGF como un agente anticolestásico altamente eficiente

The hepatocyte growth factor induces an anti-inflammatory and repairing response in the cholestasis-induced colon damage

Aim: Cholestasis remains a partially characterized disease. Evidence has been gained that it is a systemic disease that begins in the liver but significantly impacts other organs and systems such as the kidney, heart, and intestine, among others. One of the primary damage mechanisms is the generation of reactive oxygen species (ROS), which eventually leads to oxidative stress, impacting canalicular morphology and actin cytoskeleton changes that could worsen the problem. These characteristics are also observed in the kidney and intestine. The work focused on addressing the intestine effects of intrahepatic cholestasis induced by α-naphthyl isothiocyanate (ANIT) and the protective response of the hepatocyte growth factor (HGF). Methods: The 10- to 12-week-old CD1 male mice were treated with ANIT and then treated or not with HGF; intestine damage was addressed by histology, immunohistochemistry (IHC) of specific markers, oxidative stress, and apoptosis. Results: Results show changes in the intestine histology, particularly the colon and ileum, induced by the cholestasis. HGF treatment restored the histology presentation and reverted the oxidative damage, clearly indicating a healing response. This observation was supported by an increment in anti-inflammatory macrophages (CD163+) in the HGF treatment. Conclusions: The data prove that HGF induces a protective and repairing response in the intestine under cholestatic challenges

Caracterización de los efectos de protección hepática y renal del factor de crecimiento de hepatocitos en la colestasis intrahepática

La colestasis es un síndrome clínico común a un gran numero de hepatopatías, en la que la producción de bilis o su tránsito a través del tracto biliar se ve afectada debido a causas funcionales u obstructivas; la consiguiente retención intracelular de los componentes biliares tóxicos genera daños en el parénquima, en gran medida a través de mecanismos oxidantes mediados por el estrés. El factor de crecimiento de hepatocitos (HGF) y su receptor c-Met representan la primera línea de defensa contra los factores hepatotóxicos, al inducir la activación de Nrf2 que, a su vez, conduce a una respuesta antioxidante y reparadora. En este estudio, evaluamos la capacidad del HGF para contrarrestar el daño causado por el agente colestásico modelo, α-naftil isotiocianato (ANIT). HGF tuvo claros efectos anti-colestáticos, como se desprende de la mejora tanto en el flujo de bilis como en las pruebas de función hepática. El examen histológico reveló una reducción significativa de las áreas lesionadas. HGF también conservó la estructura de las uniones estrechashepatocelulares. Estos efectos anticolestásicos se asociaron con la inducción de transportadores ABC de flujo basolateral, lo que facilita la extrusión de compuestos biliares tóxicos y su posterior depuración alternativa a través de la orina. El epiteliobiliar parece haberse preservado también, como lo sugiere una normalizacióndelos niveles séricos de GGT, laexpresión de CFTR ylaestructura del cilio primario de los colangiocitos. Finalmente, reportamos que HGF también protege a los riñones y su función del deterioro producidopor la colestasis inducida por ANIT(nefropatía colémica). En conclusión, los resultados muestran claramente por primera vez que HGF protege el hígado y los riñones de una lesión colestásica

Mediterranean-like mix of fatty acids induces cellular protection on lipid-overloaded hepatocytes from western diet fed mice

Introduction and objective. Non-alcoholic fatty liver disease remains as one of the main liver disorders worldwide. It is widely accepted that is the kind of lipid, rather than the amount deposited in the cells that determines cell damage. Cholesterol and saturated free fatty acids are deleterious lipids when accumulated but, in contrast, there are some valuable lipids that could counteract those with harmful properties. Much of this knowledge arises from studies using a single fatty acid, but the effects of a combination of fatty acids, as obtained by diet has been poorly addressed. In the present work, we were focused to figure out the cellular effect of two different mixes of fatty acids, one with high proportion of saturated fatty acids, and another one with high proportion of unsaturated fatty acids (Mediterranean-like) in a cellular model of steatosis. Material and methods. Primary mouse hepatocytes from animals fed with a western diet (high fat and carbohydrates diet), were treated with both mixes of fatty acids for 24 h. Results. Our data clearly show that only the high unsaturated fatty acid mix induced a decrease in triglycerides (47.5%) and cholesterol (59%) content in steatotic hepatocytes mediating cellular protection associated to the decrement of ROS and oxidative damage. The mixture of high saturated fatty acids exhibited no effects, preserving high levels of cholesterol and triglycerides and oxidative damage. In conclusion, our results show that Mediterranean-like mix of fatty acids exerts cellular protection in steatosis by decreasing triglycerides, cholesterol, ROS content and oxidative damage

Cholangiocyte death in ductopenic cholestatic cholangiopathies: Mechanistic basis and emerging therapeutic strategies

Among hepatic diseases, cholestatic ductopenic cholangiopathies are poorly studied, and they are rarely given the importance they deserve, especially considering their high incidence in clinical practice. Although cholestatic ductopenic cholangiopathies have different etiologies and pathogenesis, all have the same target (the cholangiocyte) and similar mechanistic basis of cell death. Cholestatic cholangiopathies are characterized, predominantly, by obstructive or functional damage in the biliary epithelium, resulting in an imbalance between proliferation and cholangiocellular death; this leads to the progressive disappearance of bile ducts, as has been shown to occur in primary sclerosing cholangitis, primary biliary cholangitis, low-phospholipid-associated cholelithiasis syndrome, cystic fibrosis-related liver disease, and drug-induced ductopenia, among other biliary disorders. This review summarizes the features of the more common ductopenic syndromes and the cellular mechanisms involved in cholengiocellular death, with focus on the main forms of cholangiocyte death described so far, namely apoptosis, autophagy, necrosis, and necroptosis. It also emphasizes the importance to study in depth the molecular mechanisms of cholengiocyte death to make possible to counteract them with therapeutic purposes. These therapeutic strategies are limited in number and efficacy at present, and this is why it is important to find complementary, safe strategies to stimulate cholangiocellular proliferation in order favor bile duct replenishment as well. Successful in finding appropriate treatments would prevent the patient from having liver transplantation as the only therapeutic alternative.Fil: Salas Silva, Soraya. Universidad Autónoma Metropolitana; MéxicoFil: Simoni Nieves, Arturo. Universidad Autónoma Metropolitana; MéxicoFil: Lopez Ramirez, Jocelyn. Universidad Autónoma Metropolitana; MéxicoFil: Bucio, Leticia. Universidad Autónoma Metropolitana; México. Instituto Nacional de Cardiología Ignacio Chavez; México. Universidad Nacional Autónoma de México; MéxicoFil: Gómez Quiroz, Luis E.. Universidad Autónoma Metropolitana; México. Instituto Nacional de Cardiología Ignacio Chavez; México. Universidad Nacional Autónoma de México; MéxicoFil: Gutiérrez Ruiz, María Concepción. Universidad Autónoma Metropolitana; México. Instituto Nacional de Cardiología Ignacio Chavez; México. Universidad Nacional Autónoma de México; MéxicoFil: Roma, Marcelo Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentin

Fructose Consumption and Hepatocellular Carcinoma Promotion

Hepatocellular carcinoma (HCC) accounts for 85% of primary liver cancer, the third most common cause of cancer-related deaths worldwide. Its incidence has been increasing in both men and women. In Western countries, high-calorie diets, mainly rich in carbohydrates such as fructose, represent a significant concern due to their repercussions on the population’s health. A high-fructose diet is related to the development of Metabolic-Associated Fatty Liver Disease (MAFLD), formerly named Non-Alcoholic Fatty Liver Disease (NAFLD), and the progression of HCC as it potentiates the lipogenic pathway and the accumulation of lipids. However, fructose metabolism seems to be different between the stages of the disease, carrying out a metabolic reprogramming to favor the proliferation, inflammation, and metastatic properties of cancer cells in HCC. This review focuses on a better understanding of fructose metabolism in both scenarios: MAFLD and HCC

HGF induces protective effects in α-naphthylisothiocyanate-induced intrahepatic cholestasis by counteracting oxidative stress

Cholestasis is a clinical syndrome common to a large number of hepatopathies, in which either bile production or its transit through the biliary tract is impaired due to functional or obstructive causes; the consequent intracellular retention of toxic biliary constituents generates parenchyma damage, largely via oxidative stress-mediated mechanisms. Hepatocyte growth factor (HGF) and its receptor c-Met represent one of the main systems for liver repair damage and defense against hepatotoxic factors, leading to an antioxidant and repair response. In this study, we evaluated the capability of HGF to counteract the damage caused by the model cholestatic agent, α-naphthyl isothiocyanate (ANIT). HGF had clear anti-cholestatic effects, as apparent from the improvement in both bile flow and liver function test. Histology examination revealed a significant reduction of injured areas. HGF also preserved the tight-junctional structure. These anticholestatic effects were associated with the induction of basolateral efflux ABC transporters, which facilitates extrusion of toxic biliary compounds and its further alternative depuration via urine. The biliary epithelium seems to have been also preserved, as suggested by normalization in serum GGT levels, CFTR expression and cholangyocyte primary cilium structure our results clearly show for the first time that HGF protects the liver from a cholestatic injury.Fil: Salas Silva, Soraya. Universidad Autónoma Metropolitana; MéxicoFil: Simoni Nieves, Arturo. Universidad Autónoma Metropolitana; MéxicoFil: Razori, María Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; ArgentinaFil: López Ramirez, Jocelyn. Universidad Autónoma Metropolitana; MéxicoFil: Barrera Chimal, Jonatan. Universidad Nacional Autónoma de México; MéxicoFil: Lazzarini, Roberto. Universidad Autónoma Metropolitana; MéxicoFil: Bello, Oscar. Universidad Autónoma Metropolitana; MéxicoFil: Souza, Verónica. Universidad Autónoma Metropolitana; MéxicoFil: Miranda Labra, Roxana U.. Universidad Autónoma Metropolitana; MéxicoFil: Gutiérrez Ruiz, María Concepción. Universidad Autónoma Metropolitana; MéxicoFil: Gomez Quiroz, Luis Enrique. Universidad Autónoma Metropolitana; MéxicoFil: Roma, Marcelo Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; ArgentinaFil: Bucio Ortiz, Leticia. Universidad Autónoma Metropolitana; Méxic

The Consumption of Cholesterol-Enriched Diets Conditions the Development of a Subtype of HCC with High Aggressiveness and Poor Prognosis

International audienceNon-alcoholic fatty liver disease (NAFLD) and progression to non-alcoholic steatohepatitis (NASH) result as a consequence of diverse conditions, mainly unbalanced diets. Particularly, high-fat and cholesterol content, as well as carbohydrates, such as those commonly ingested in Western countries, frequently drive adverse metabolic alterations in the liver and promote NAFLD development. Lipid liver overload is also one of the main risk factors for initiation and progression of hepatocellular carcinoma (HCC), but detailed knowledge on the relevance of high nutritional cholesterol remains elusive. We were aimed to characterize HCC development in mice fed with a Western diet (high in lipids and cholesterol) and to identify molecular alterations that define a subtype of liver cancer induced by lipid overload. Mice under western or high cholesterol diets more frequently developed tumors with a more aggressive phenotype than animals fed with a chow diet. Associated changes involved macrophage infiltration, angiogenesis, and stemness features. RNA-seq revealed a specific gene expression signature ( and ) resembling the adverse phenotypic features and poor clinical outcomes seen in patients with HCC. In conclusion; consumption of lipid enriched diets; particularly cholesterol; could accelerate HCC development with an aggressive phenotype and poor prognosis