In this study, we attempted to use lactoferrin to improve HFCSinduced HMMS including hepatic steatosis, insulin resistance, inflammation and oxidative stress in a murine model. In the western diet, long-term consumption of beverages containing HFCS contributes to the development HMMS, including obesity, insulin resistance, hypertriglyceridemia, NAFLD, and NASH, all of which are associated with an inflammatory state. Previous studies have indicated that administration of 15-54% aqueous solutions of HFCS can elevate fasting blood glucose concentrations and increase insulin resistance in murine models. Inflammatory status indicates the progression of obesity, insulin resistance, NAFLD, and NASH. In this study, gross examination of the livers of HFCSadministered mice showed lipid accumulation and a 45% increase in liver weight. Microscopic examination of liver sections revealed steatosis after HFCS administration, which was significantly reduced in a dosedependent manner by lactoferrin treatment. HFSC stimulates overgrowth of intestinal microbiota, increasing intestinal permeability and leading to chronic inflammation. In this study, HFCS induced overgrowth of fecal coliforms and higher serum LPS. Our data indicate that lactoferrin altered the HFCS-induced imbalance in intestinal microbiota and reduced chronic inflammation. In previous studies, lactoferrin presents to exert anti-infectious and anti-inflammatory activities in vivo, and to inhibit LPS-induced IL6 secretion in a human monocytic cell line. This observation was extended with a demonstration that lactoferrin inhibits the expression of mRNA of proinflammatory cytokines, including TNF-a, IL-1, IL-6, and IL-8, and modulates the nuclear transcription factor kappa B signaling cascade. Lactoferrin has also been shown to downregulate IL-10 secretion in LPS-stimulated macrophages. In our study, serum and hepatic LPS levels significantly increased in HFCS-induced HMMS, and this increase was significantly reduced IL-10 by lactoferrin. Significantly, reduced expression of TLR-4 was also observed in lactoferrin-treated groups indicated the reducing inflammatory cascade signaling. Puddu et al., indicate bovine lactoferrin conteracts TLR mediated activation signals in monocyte-derived dendritic cells. Serum ALT is a direct indicator of hepatitis, and lactoferrin reduced sALT in a dose-dependent manner. Furthermore, cytokine measurements indicated that lactoferrin could significantly reduce hepatic IL-1b, TNF-a, and MCP-1. Previous studies have shown that lactoferrin can bind LPS from E. coli and Salmonella typhimurium and remove the glycolipid from the bacterial surface. Lactoferricin, a peptide produced by hydrolysis of lactoferrin by a gastrointestinal digestive enzyme, plays a central role in scavenging LPS. Analysis of the structural characteristics of lactoferricin identified a six-residue sequence responsible for binding LPS of E. coli or Pseudomonas aeruginosa.