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Santa Maria Imbaro, Italy

Gadaleta R.M.,University Utrecht | Gadaleta R.M.,Laboratory of Lipid Metabolism and Cancer | van Mil S.W.C.,University Utrecht | Oldenburg B.,University Utrecht | And 3 more authors.
Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids | Year: 2010

The nuclear receptor Farnesoid X Receptor (FXR) critically regulates nascent bile formation and bile acid enterohepatic circulation. Bile acids and FXR play a pivotal role in regulating hepatic inflammation and regeneration as well as in regulating extent of inflammatory responses, barrier function and prevention of bacterial translocation in the intestinal tract. Recent evidence suggests, that the bile acid-FXR interaction is involved in the pathophysiology of a wide range of diseases of the liver, biliary and gastrointestinal tract, such as cholestatic and inflammatory liver diseases and hepatocellular carcinoma, inflammatory bowel disease and inflammation-associated cancer of the colon and esophagus. In this review we discuss current knowledge of the role the bile acid-FXR interaction has in (patho)physiology of the liver, biliary and gastrointestinal tract, and proposed underlying mechanisms, based on in vitro data and experimental animal models. Given the availability of highly potent synthetic FXR agonists, we focus particularly on potential relevance for human disease. © 2010 Elsevier B.V. All rights reserved.

Modica S.,Laboratory of Lipid Metabolism and Cancer
Nuclear receptor signaling | Year: 2010

Originally called retinoid X receptor interacting protein 14 (RIP14), the farnesoid X receptor (FXR) was renamed after the ability of its rat form to bind supra-physiological concentrations of farnesol. In 1999 FXR was de-orphanized since primary bile acids were identified as natural ligands. Strongly expressed in the liver and intestine, FXR has been shown to be the master transcriptional regulator of several entero-hepatic metabolic pathways with relevance to the pathophysiology of conditions such as cholestasis, fatty liver disease, cholesterol gallstone disease, intestinal inflammation and tumors. Furthermore, given the importance of FXR in the gut-liver axis feedbacks regulating lipid and glucose homeostasis, FXR modulation appears to have great input in diseases such as metabolic syndrome and diabetes. Exciting results from several cellular and animal models have provided the impetus to develop synthetic FXR ligands as novel pharmacological agents. Fourteen years from its discovery, FXR has gone from bench to bedside; a novel nuclear receptor ligand is going into clinical use.

Moschetta A.,Laboratory of Lipid Metabolism and Cancer | Moschetta A.,University of Bari
Cancer Discovery | Year: 2011

Both primary and transformed cells need cholesterol for their growth. Guo and colleagues unraveled the connection between epidermal growth factor receptor mutations in glioblastoma and increased cholesterol influx via sterol regulatory element-binding protein 1 and low-density lipoprotein receptor (LDLR) increase. They propose the activation of the liver X receptor-inducible degrader of LDLR-LDLR axis as a therapeutic approach to reduce intracellular cholesterol, block tumor growth, and induce cell death. © 2011 American Association for Cancer Research.

Cicione C.,Laboratory of Lipid Metabolism and Cancer | Degirolamo C.,Laboratory of Lipid Metabolism and Cancer | Moschetta A.,Laboratory of Lipid Metabolism and Cancer | Moschetta A.,University of Bari | Moschetta A.,Italian National Cancer Institute
Hepatology | Year: 2012

Fibroblast growth factors (FGFs) 15/19 and 21 belong to the FGF endocrine subfamily. They present the intriguing characteristic to be transcribed and secreted in certain tissues and to act as hormones. The insulin-mimetic properties of FGF21 and the regulatory role of FGF15/19 in bile acid and glucose homeostasis endorse these hormones as druggable targets in metabolic disorders. Here, we present details on discoveries, identification, transcriptional regulation, and mechanism of actions of FGF15/19 and FGF21 with a critical perspective view on their putative role as metabolic integrators in the liver. © 2012 American Association for the Study of Liver Diseases.

Bonamassa B.,Laboratory of Lipid Metabolism and Cancer | Moschetta A.,Laboratory of Lipid Metabolism and Cancer | Moschetta A.,University of Bari | Moschetta A.,Italian National Cancer Institute | Moschetta A.,National Institute for Digestive Diseases
Trends in Endocrinology and Metabolism | Year: 2013

Modulation of the cholesterol-sensing liver X receptors (LXRs) and their downstream targets has emerged as promising therapeutic avenues in atherosclerosis. The intestine is important for its unique capabilities to act as a gatekeeper for cholesterol absorption and to participate in the process of cholesterol elimination in the feces and reverse cholesterol transport (RCT). Pharmacological and genetic intestine-specific LXR activation have been shown to protect against atherosclerosis. In this review we discuss the LXR-targeted molecular players in the enterocytes as well as the intestine-driven pathways contributing to cholesterol homeostasis with therapeutic potential as targets in the prevention and treatment of atherosclerosis. © 2012 Elsevier Ltd.

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