Increased Liver Localization of Lipopolysaccharides in Human and Experimental NAFLD

Guido Carpino¹, Maria Del Ben², Daniele Pastori², Roberto Carnevale^{3 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 Violi^{2 4}

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.