Abstract
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.
Highlights
Nonalcoholic fatty liver disease (NAFLD) comprises a spectrum of liver histological alterations ranging from non-inflammatory isolated steatosis to nonalcoholic steatohepatitis (NASH), which is characterized by steatosis, necro-inflammatory changes and varying degrees of liver fibrosis[1, 2]
choline-deficient amino acid-defined (CDAA) diet was associated with a significant increase in liver weight, which was prevented by ANDRO treatment (Fig. 1B)
NASH can lead to advanced liver fibrosis and cirrhosis, which eventually results in liver failure[3]
Summary
Nonalcoholic fatty liver disease (NAFLD) comprises a spectrum of liver histological alterations ranging from non-inflammatory isolated steatosis to nonalcoholic steatohepatitis (NASH), which is characterized by steatosis, necro-inflammatory changes and varying degrees of liver fibrosis[1, 2]. Type 2 diabetes mellitus and cardiovascular risk factors[5] and those with NASH have an increased liver-related mortality due to the progression to cirrhosis and its complications including hepatocellular carcinoma[3]. There has been a renewed interest in the therapeutic potential of herbal remedies for liver diseases including NAFLD9. Pre-clinical studies with some of these agents have shown that they are able to modulate insulin resistance, lipid metabolism, oxidative stress, inflammation, and necro-apoptosis, all key factors in NAFLD/NASH pathogenesis[10]. Translation of this knowledge into the clinic has been rather limited. ANDRO’s mechanism of action are diverse and include antioxidant capacity, modulation of nitric oxide and prostaglandin production, modulatory action of immune cells and inhibitory effects on NF-kappa B (NF-κB) transcription factor[12, 14]
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