Andrographolide Ameliorates Inflammation and Fibrogenesis and Attenuates Inflammasome Activation in Experimental Non-Alcoholic Steatohepatitis

• Published in: Scientific reports Vol. 7; no. 1; pp. 3491 - 12
• Main Authors: Cabrera, Daniel, Wree, Alexander, Povero, Davide, Solís, Nancy, Hernandez, Alejandra, Pizarro, Margarita, Moshage, Han, Torres, Javiera, Feldstein, Ariel E, Cabello-Verrugio, Claudio, Brandan, Enrique, Barrera, Francisco, Arab, Juan Pablo, Arrese, Marco
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 14.06.2017; Nature Publishing Group UK; Nature Portfolio
• Subjects: Alanine; Animals; Anti-inflammatory agents; Anti-Inflammatory Agents, Non-Steroidal - administration & dosage; Cells, Cultured; Choline; Diterpenes - administration & dosage; Fibrosis; Fibrosis - prevention & control; Inflammasomes; Inflammasomes - metabolism; Inflammation; Inflammation - complications; Inflammation - metabolism; Inflammation - prevention & control; Lipopolysaccharides; Liver; Macrophages; Macrophages - drug effects; Male; Mice, Inbred C57BL; mRNA; NF-kappa B - metabolism; NF-κB protein; Non-alcoholic Fatty Liver Disease - complications; Rats, Wistar; Rodents; Serum levels; Transcription activation
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-03675-z

Therapy for nonalcoholic steatohepatitis (NASH) is limited. Andrographolide (ANDRO), a botanical compound, has a potent anti-inflammatory activity due to its ability to inhibit NF-κB. ANDRO has been also shown to inhibit the NLRP3 inflammasome, a relevant pathway in NASH. Our aim was to evaluate the effects of ANDRO in NASH and its influence on inflammasome activation in this setting. Thus, mice were fed a choline-deficient-amino-acid-defined (CDAA) diet with/without concomitant ANDRO administration (1 mg/kg, 3-times/week). Also, we assessed serum levels of alanine-aminotransferase (ALT), liver histology, hepatic triglyceride content (HTC) and hepatic expression of pro-inflammatory, pro-fibrotic and inflammasome genes. Inflammasome activation was also evaluated in fat-laden HepG2 cells. Our results showed that ANDRO administration decreased HTC and attenuated hepatic inflammation and fibrosis in CDAA-fed mice. ANDRO treatment determined a strong reduction in hepatic macrophage infiltration and reduced hepatic mRNA levels of both pro-inflammatory and pro-fibrotic genes. In addition, mice treated with ANDRO showed reduced expression of inflammasome genes. Finally, ANDRO inhibited LPS-induced interleukin-1β expression through NF-κB inhibition in fat-laden HepG2 cells and inflammasome disassembly. In conclusion, ANDRO administration reduces inflammation and fibrosis in experimental NASH. Inflammasome modulation by a NF-κB-dependent mechanism may be involved in the therapeutic effects of ANDRO.