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

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.

Attenuation of the Hepatoprotective Effects of Ileal Apical Sodium Dependent Bile Acid Transporter (ASBT) Inhibition in Choline-Deficient L-Amino Acid-Defined (CDAA) Diet-Fed Mice

“…The CDAA diet has been shown to successfully induce fibrosis after feeding for 22 weeks (18,19,31). To visualize fibrosis on histology, collagen was stained with Sirius Red.…”

The NLRP3 Inflammasome in Alcoholic and Nonalcoholic Steatohepatitis

“…71,72 The working group of Cabrera found that Andrographolide, a botanical compound, decreased NLRP3 inflammasome activation, inflammatory immune cell infiltration, and expression of fibrotic proteins in CDAA-induced NASH by suppression of NF-κB. 73 Recently, a few drugs have been developed, which directly target the NLRP3 inflammasome, but only one has been analyzed regarding its efficacy in experimental NASH. MCC950, a substance that belongs to the family of cytokine release inhibitory drugs, blocks canonical and noncanonical activation of NLRP3 inflammasome at nanomolar concentrations.…”

Intestinally derived bacterial products stimulate development of nonalcoholic steatohepatitis

“…LPS, transported via TLR4-dependent pathway, can play an important function for patients with NASH who have previous history of benign steatosis [38,39]. In fact, several studies have investigated how to counteract and reverse the pro-inflammatory and lipogenic effects of LPS [40][41][42][43][44][45]. These data imply that liver damage can occur when hepatic immune cells are exposed to TLR ligands [46][47][48].…”

“…If an article contained a reference that had not been detected in the search or general reading, this reference was obtained. A, Reviews 5,6,8,9,13,[17][18][19][20][21][22]26,29,31,32,35,36,38,47,54,56,57,67,90,91,94,97,100,103,106,107,125,138 B, In vitro studies 30,39,[41][42][43][44]49,53,62,64,65,[73][74][75]89,93,110,116,…”