Guido Carpino1, Maria Del Ben2, Daniele Pastori2, Roberto Carnevale3,4, Francesco Baratta2, Diletta Overi5, Heather Francis6, Vincenzo Cardinale3, Paolo Onori5, Samira Safarikia7, Vittoria Cammisotto8, Domenico Alvaro7, Gianluca Svegliati-Baroni9, Francesco Angelico10, Eugenio Gaudio5, Francesco Violi2,4. 1. Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome "Foro Italico,", Rome, Italy. 2. Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy. 3. Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy. 4. Mediterranea Cardiocentro, Naples, Italy. 5. Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy. 6. Indiana Center for Liver Research, Richard L. Roudebush VA Medical Center and Indiana University, Indianapolis, IN. 7. Department of Precision and Translational Medicine, Sapienza University of Rome, Rome, Italy. 8. Department of General Surgery and Surgical Specialty Paride Stefanini, Sapienza University of Rome, Rome, Italy. 9. Department of Gastroenterology and Hepatology, Marche Polytechnic University, Ancona, Italy. 10. Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy.
Abstract
BACKGROUND AND AIMS: Lipopolysaccharides (LPS) is increased in nonalcoholic fatty liver disease (NAFLD), but its relationship with liver inflammation is not defined. APPROACH AND RESULTS: We studied Escherichia coli LPS in patients with biopsy-proven NAFLD, 25 simple steatosis (nonalcoholic fatty liver) and 25 nonalcoholic steatohepatitis (NASH), and in mice with diet-induced NASH. NASH patients had higher serum LPS and hepatocytes LPS localization than controls, which was correlated with serum zonulin and phosphorylated nuclear factor-κB expression. Toll-like receptor 4 positive (TLR4+ ) macrophages were higher in NASH than simple steatosis or controls and correlated with serum LPS. NASH biopsies showed a higher CD61+ platelets, and most of them were TLR4+ . TLR4+ platelets correlated with serum LPS values. In mice with NASH, LPS serum levels and LPS hepatocyte localization were increased compared with control mice and associated with nuclear factor-κB activation. Mice on aspirin developed lower fibrosis and extent compared with untreated ones. Treatment with TLR4 inhibitor resulted in lower liver inflammation in mice with NASH. CONCLUSIONS: In NAFLD, Escherichia coli LPS may increase liver damage by inducing macrophage and platelet activation through the TLR4 pathway.
BACKGROUND AND AIMS: Lipopolysaccharides (LPS) is increased in nonalcoholic fatty liver disease (NAFLD), but its relationship with liver inflammation is not defined. APPROACH AND RESULTS: We studied Escherichia coli LPS in patients with biopsy-proven NAFLD, 25 simple steatosis (nonalcoholic fatty liver) and 25 nonalcoholic steatohepatitis (NASH), and in mice with diet-induced NASH. NASHpatients had higher serum LPS and hepatocytes LPS localization than controls, which was correlated with serum zonulin and phosphorylated nuclear factor-κB expression. Toll-like receptor 4 positive (TLR4+ ) macrophages were higher in NASH than simple steatosis or controls and correlated with serum LPS. NASH biopsies showed a higher CD61+ platelets, and most of them were TLR4+ . TLR4+ platelets correlated with serum LPS values. In mice with NASH, LPS serum levels and LPS hepatocyte localization were increased compared with control mice and associated with nuclear factor-κB activation. Mice on aspirin developed lower fibrosis and extent compared with untreated ones. Treatment with TLR4 inhibitor resulted in lower liver inflammation in mice with NASH. CONCLUSIONS: In NAFLD, Escherichia coli LPS may increase liver damage by inducing macrophage and platelet activation through the TLR4 pathway.