Lactoferrin ameliorates non-alcoholic fatty liver disease by modulating hepatic sensitivity to fibroblast growth factor 21

Lactoferrin (LF) exerts beneficial effects in against various metabolic disorders including nonalcoholic fatty liver disease (NAFLD). In this study, we investigated the effect of LF supplementation on hepatic sensitivity to fibroblast growth factor 21 (FGF21) in NAFLD and further elucidate the underlying molecular mechanisms. We found that LF supplementation significantly ameliorated glucose and lipid metabolic disorders, and attenuated hepatic steatosis in mice fed a high-fat diet (HFD). Moreover, LF supplementation reduced both hepatic and serum FGF21 levels, concomitantly down-regulated hepatic phosphorylated p38 (p-p38) expression and up-regulated the hepatic expression of KLB. Moreover, the combined intervention of LF and recombinant mouse FGF21 (rmFGF21) showed a modest additive improvement in insulin sensitivity and hepatic function compared with LF or rmFGF21 alone. Notably, these effects were largely abrogated in Fgf21- knockout mice. LF may enhance hepatic sensitivity to FGF21 by down-regulating p-p38 expression and up-regulating β-klotho (KLB) expression in HFD-fed mice, thereby ameliorating lipid metabolic disorders and insulin resistance in murine model of NAFLD.