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We would like to thank Dr. Alisi and colleagues for their interest in our recent manuscript detailing the relationship between Kupffer cell-derived interleukin 12 (IL12) production and loss of hepatic natural killer T (NKT) cells in the steatotic liver.1 It is clear from our study and several others that NKT cells are highly sensitive to hepatic lipid accumulation, a process which we can link to IL12 production by Kupffer cells.1-4 In response to their first comment, we expected that if NKT cells were restored, hepatic lipid accumulation would also be reduced; we were very surprised to see otherwise. Indeed, these results in this model of nonalcoholic fatty liver suggest that NKT cell depletion is a consequence of lipid accumulation and Kupffer cell activation, which challenges the notion that they function to suppress hepatocellular lipid accumulation in nonalcoholic fatty liver disease. As for the mechanism(s) governing IL12 production by Kupffer cells in the nonalcoholic fatty liver, a number of potential possibilities exist with gut-liver interactions being a strong candidate. There is no doubt that gut-derived factors, including gut-derived lipopolysaccharide, contribute to Kupffer cell activation and IL12 production. Recent studies by Ma and colleagues have demonstrated the ability of probiotics, which likely alter gut microbial populations, to protect the hepatic NKT cells within the steatotic liver.5 In addition, it has been shown that Toll-like receptor-9 engagement can promote Kupffer cell-dependent and IL12-dependent NKT cell recruitment to the nonsteatotic liver and exacerbate concanavalin A-mediated hepatitis.6 This highlights the potential impact of gut-derived factors, including bacterial DNA, as key regulators of NKT cell function, although their direct influence on NKT cells within the steatotic liver remains to be determined. It is very likely that a combination of hepatocellular lipid accumulation and Kupffer cell activation promote this response. This complex association is evidenced by data from our study where isolated Kupffer cells from the steatotic liver do not produce more IL12 than those Kupffer cells isolated from a normal liver when activated in vitro, despite showing large and significant increases in its production when activated by lipopolysaccharide in vivo.1 Thus, multiple levels of regulation likely exist and gut-derived antigens no doubt contribute at least in part to this process. Current studies are directed at better understanding the mechanism(s) of Kupffer cell activation and IL12 production, as well as the potential contribution of gut-derived factors in this model of nonalcoholic fatty liver disease. Ian N. Hines Ph.D.*, * Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, NC.