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    Introduction Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver diseases ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), which may further progress to liver cirrhosis and liver carcinoma [1], [2]. While hepatic steatosis is considered a benign condition, a “two-hit” theory has been proposed to explain the pathogenesis of NAFLD [3], [4]. The first hit consists of abnormal accumulation of triglycerides (TG) in the liver. If steatotic liver suffers a second hit, including inflammatory mediators, reactive oxygen species, and activation of stellate cells, it may progress to NASH. NAFLD is often associated with obesity and diabetes and is also an independent risk factor for cardiovascular disease [5], [6], [7], [8]. Bile acids (BAs) are amphipathic molecules. Primary BAs are synthesized from cholesterol exclusively in the liver whereas secondary BAs are synthesized in the intestine. BAs help find out this here of dietary lipids from the intestine and are endogenous ligands for the nuclear receptor farnesoid X receptor (FXR) and the G protein-coupled receptor bile acid receptor TGR5 (also called GPBAR1). Chenodeoxycholic acid and lithocholic acid are the most potent endogenous activators of FXR and TGR5, respectively, while cholic acid is the least potent activator of both receptors [1]. Nonetheless, BA can also activate other nuclear receptors or pathways [9]. The two BA receptors have overlapping but also differing tissue and cell distributions. FXR is mostly expressed in the liver (hepatocytes only), intestine, kidney, and adrenal glands [10] while TGR5 has a wider expression pattern including gallbladder, small intestine, brown adipose tissue (BAT), spleen, and macrophages [11]. In the liver, TGR5 is only expressed in sinusoidal endothelial cells and Kupffer cells, the resident macrophages of the liver, but not in hepatocytes [12]. Many lines of evidence have clearly demonstrated that activation of FXR improves lipid and glucose homeostasis and inhibits the development of NAFLD and atherosclerosis [1], [13]. Activation of TGR5 improves glucose and energy homeostasis and inhibits atherogenesis by inducing glucagon-like peptide-1 (GLP-1) secretion in the intestine and thermogenic genes in BAT and skeletal muscle [14], [15] and suppressing macrophage inflammation [16]. However, long-term activation of FXR can also induce obesity by reducing the BA pool size [17]. In addition, activation of TGR5 appears to have a limited impact on lipid homeostasis [16]. Thus, development of dual agonist(s) for both FXR and TGR5 appears to be a more attractive strategy for treatment of common metabolic disorders. INT-767 is a semisynthetic, potent, and specific agonist for both FXR and TGR5, with EC50 values of 30 nM and 630 nM, respectively [18]. INT-767 reduces monocyte infiltration and inhibits NASH development in db/db mice [19] and suppresses the development of atherosclerosis in Apoe−/− mice [20]. So far, it is unclear whether INT-767 treatment can reverse diet-induced metabolic disorders or atherosclerosis and how INT-767 treatment improves metabolic disorders. In this report, we utilized wild-type (WT) mice, Fxr−/− mice, and Tgr5−/− mice to elucidate the relative importance of FXR versus TGR5 in INT-767-regulated metabolic homeostasis. We also utilized small heterodimer partner (Shp) knockout (Shp−/−) mice to address how activation of FXR inhibits lipogenic genes. In addition, we investigated whether INT-767 could reverse atherosclerosis in Apoe−/− mice. Our data indicate that INT-767 reverses obesity, hypercholesterolemia, NAFLD, and atherosclerosis by activation of FXR and/or TGR5. Dual find out this here activation of FXR and TGR5 is an attractive strategy for treatment of common metabolic disorders.
    Materials and methods