A two-hit theory has been proposed and environmental chemicals may represent the second hit. Historically, NAFLD and NASH were attributed, in part, to the inappropriate over- or under-activation of nuclear receptors involved in endobiotic metabolism, including the liver-X-receptor (Lxr), farnesoid-X-receptor (Fxr), and peroxisome proliferator-activated receptors (Ppars) that regulate cholesterol, bile acid and lipid metabolism respectively (Mangelsdorfetal., 1995; Novac and Heinzel, 2004). activity in both knockouts, and decreased food consumption in theCar/mice. Aroclor exposure improved insulin sensitivity in WT mice but not glucose tolerance. The Aroclor-exposed, Pxr/mice displayed increased gluconeogenic gene expression. Lipid-oxidative gene expression was higher in WT andPxr/mice although RER was not changed, suggesting PCB-mediated mitochondrial dysfunction. Therefore , Pxr and Car regulated inflammation, behavior, and energy metabolism in PCB-mediated NASH. Future studies should address the off-target effects of PCBs in steatohepatitis. Keywords: Aroclor 1260, PCBs, nuclear receptors, energy metabolism, steatohepatitis Non-alcoholic fatty liver disease (NAFLD) refers to a pathological spectrum of physiological disorders ranging from Rabbit polyclonal to PAI-3 lipid accumulation in hepatocytes (steatosis) to the development of superimposed inflammation, resulting in non-alcoholic-steatohepatitis (NASH), and ultimately fibrosis and cirrhosis. NAFLD is associated with multiple metabolic derangements and systemic responses, including: (1) obesity and its related sedentary lifestyle behaviors; (2) hepatic responses primarily steatosis (possibly a reflection of abnormal lipid and carbohydrate metabolism), inflammation and fibrosis; and (3) diabetes and insulin resistance. Typically, these metabolic derangements occur consecutively such that excessive caloric intake coupled with decreased exercise leads to hepatic steatosis and inflammation, resulting in worsened insulin resistance and the metabolic syndrome. However , these phenomena can become dissociated wherein lean patients may develop NASH; only some NASH patients develop diabetes; and some patients develop only steatosis and never progress to steatohepatitis and fibrosis. A two-hit theory has been proposed and environmental chemicals may represent the second hit. Rotundine Historically, NAFLD and NASH were attributed, in part, to the inappropriate over- or under-activation of nuclear receptors involved in endobiotic metabolism, including the liver-X-receptor (Lxr), farnesoid-X-receptor (Fxr), and peroxisome proliferator-activated receptors (Ppars) that regulate cholesterol, bile acid and lipid metabolism respectively (Mangelsdorfet al., 1995; Novac and Heinzel, 2004). The role of hepatic receptors involved in xenobiotic detoxification, namely the pregnane-xenobiotic receptor (Pxr), constitutive androstane receptor (Car), and aryl hydrocarbon receptor (Ahr) have more recently been associated with NAFLD/NASH. Although thought to be involved in xenobiotic metabolism, receptor over-activation or antagonism may lead to metabolic diseases (Klieweret al., 2002; Konnoet al., 2008; Merrell and Cherrington, 2011; Moyaet al., 2010; Weiet al., 2000). Recent studies have demonstrated these receptors role in energy homeostasis, including regulation of lipid and carbohydrate metabolism (Konnoet al., 2008; Wadaet al., 2009). Car has been considered to be an anti-obesity nuclear receptor since its activation improves insulin sensitivity and ameliorates diabetes and NAFLD (Donget al., 2009; Gaoet al., 2009). Furthermore, Pxr and Car activation also suppresses gluconeogenesis by decreasing gluconeogenic gene expression most likely through the sequestration of forkhead boxO1 (Foxo1) (Kodamaet al., 2004, 2007). The reported role of Pxr in obesity is controversial with some studies demonstrating obesity-protecting effects of Pxr (Ma and Liu, 2012) and others illustrating that ablatingPxralleviated diet-induced obesity (Fernandezet al., 2013; Spruiellet al., 2014). Car and Pxr ligands vary from therapeutic drugs to industrial chemicals and environmental pollutants including polychlorinated biphenyls (PCBs) (Handschin and Meyer, 2003; Hernandezet al., 2009). PCBs are persistent organic pollutants manufactured in the 1930s70s and used in industrial applications. Epidemiologic studies have correlated PCB exposure with liver disease, type 2 diabetes, obesity, and related cardiovascular disorders (Silverstoneet al., 2012). Moreover, 100% of the adult National Health and Nutrition Examination Survey (NHANES) participants had detectable circulating PCB levels with PCB 153 having the highest median serum concentration (Caveet al., 2010). PCB exposures were also correlated with elevation in liver enzymes such as alanine transaminase (ALT) in the NHANES participants. Monsanto Rotundine Company, the only PCB manufacturer in North America, produced PCB mixtures under the brand name Aroclor at its manufacturing plant located in Anniston, Alabama. Incidences of high-level environmental contamination during PCB production at the time resulted in increased PCB body burden in the Anniston residents till today. Aroclor 1260 (60% chlorine by weight) was one of the early PCB mixtures produced and it was later replaced by other PCB mixtures with lower chlorine Rotundine content such as 1254, 1248, and 1242. Although being banned for over 30 years, highly chlorinated PCBs continue to persist in the environment due to their high thermodynamic stability and limited metabolism. Therefore , the profile of bio-accumulated PCBs closely resembles Aroclor 1260. Currently, PCB exposure is thought to occur primarily through ingestion of PCB contaminated food (Schecteret al., 2010), and thus,.