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  • More recently several groups have characterized a role for G


    More recently, several groups have characterized a role for GPR120 signaling via omega-3 fatty acids in amelioration of alcoholic hepatic injury and non-alcoholic fatty liver disease (NAFLD) [18], [19]. Nakamoto et al. demonstrated protective effects of the omega-3 fatty ganciclovir docosahexaenoic acid (DHA) in a choline-deficient high-fat diet murine model of NAFLD. This DHA-dependent hepatic protection from liver injury was GPR120-dependent [19]. Raptis et al. reported that fish oil-mediated GPR120 signaling can attenuate hepatic ischemia-reperfusion injury [13]. While a relationship between omega-3 fatty acid-mediated GPR120 signaling and protection of the liver from inflammatory insults has been established, the downstream cellular pathways of FOLE-mediated hepatic protection that could identify targets of pharmacologic intervention have yet to be characterized.
    Materials and methods
    Discussion and conclusions This study demonstrates that the ability of FOLE to protect the liver from PN-induced injury requires intact GPR120 expression. FOLE-mediated GPR120 signaling in this model acts, at least in part, via PPARγ. PPARγ is a transcription factor that regulates expression and activity of several cell types and organ systems. It affects not only metabolism and insulin sensitivity, but also systemic electrolyte and water balance, bone homeostasis, angiogenesis, and inflammation [21], [22], [23], [24]. The PPARγ target genes that appear to be predominantly altered by the PN diet and normalized by FOLE are CD36 and SCD1. Prior studies have established roles for omega-3 fatty acid-mediated GPR120 signaling and, independently, PPARγ in modulating hepatic lipid metabolism [25], [26], [27]. Recently, a relationship has been established between GPR120 signaling and PPARγ activity in modulating lipid metabolism and adipocyte function [28]. CD36 is a cell surface receptor that facilitates cellular uptake of fatty acids. It is a known target of PPARγ, and its increased activity has been identified in several models of fatty liver disease [29], [30], [31], [32]. SCD1 catalyzes the synthesis of monounsaturated fatty acids in the liver. It is also a known target of PPARγ, and its increased activity has been linked to the development of non-alcoholic hepatic steatosis [33], [34]. The findings of this study suggest a model in which PN promotes liver injury through PPARγ-mediated up-regulation of CD36 and SCD1; and FOLE-mediated hepatic GPR120 signaling inhibits this activity of PPARγ to protect the liver from PN-induced injury. Interestingly, GPR120 is expressed primarily on Kupffer cells in the liver with minimal expression in hepatocytes [35], while hepatic lipid metabolism takes place in hepatocytes. While this study does not address this specifically, one plausible hypothesis is that FOLE-mediated GPR120 signaling in hepatic Kupffer cells results in release of factors that act in a paracrine fashion on hepatocytes to attenuate PPARγ-mediated CD36 and SCD1 activity. Future research efforts in our laboratory are aimed at answering these questions. A limitation of this study is that the murine model of PN-induced liver injury develops steatosis, while the clinical correlate in PN-dependent patients is primarily cholestatic liver disease. This murine model has reliably recapitulated the effects of SOLE in exacerbating, and of FOLE in preventing PN-induced liver injury [6], [36], [37], [38]. Further, this model has been able to predict the effects of various intravenous lipid emulsions in patients with IFALD [7]. Studies utilizing this model have contributed to the rationale for the recent United States Food and Drug Administration's approval of FOLE for use as a fat source in PN for the treatment of IFALD. It is possible that in PN-dependent patients, hepatic inflammation and steatosis occur prior to the development of symptoms, and cholestasis and cirrhosis manifest once patients with IFALD become symptomatic. This is akin to the findings in NAFLD in which steatosis and acute inflammation precede progression to cirrhosis. Given the steatotic phenotype seen in this model, these results are highly likely to be generalizable to NAFLD and should be tested in well-established NAFLD models.