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    • Activation of FXR or TGR

    2022-06-22

    Activation of FXR or TGR5 has overlapping but also differing effects on metabolic regulation and inflammation [1]. In this report, we demonstrate that in addition to preventing the progression of obesity, NAFLD, and atherosclerosis, activation of BA receptors can also promote regression of these common metabolic disorders. Mechanistically, we demonstrate that BA receptor activation reduces obesity, induces thermogenic genes and inhibits inflammatory response via activation of FXR and TGR5. We also demonstrate that bile minocycline hydrochloride mg receptor activation inhibits hepatic lipogenic genes and lipogenesis via activation of FXR. Given that long-term activation of FXR is reported to induce obesity [17] and that activation of TGR5 alone has a limited effect on lipid metabolism, our data suggest that targeting both FXR and TGR5 is a more attractive strategy for treatment of common metabolic disorders, such as obesity, NAFLD, and atherosclerosis. NAFLD is one of the most common liver diseases worldwide and is also an independent risk factor for cardiovascular diseases. Our data clearly show that bile acid receptor activation reduces lipogenesis and liver steatosis via activation of FXR. Although FXR activation has been shown to reduce hepatic TG levels, the underlying mechanism is not well understood [1], [40]. FXR is shown to inhibit hepatic SREBP-1c expression, but FXR does not inhibit SREBP-1c downstream target genes [1], [40], suggesting that the FXR-SREBP-1c pathway is not critical. Previously, we have shown that the induction of hepatic carboxylesterase 1 may partly account for the reduction in hepatic TG levels following FXR activation [25]. In the present study, we show that both INT-767 and specific activation of FXR by GW4064 repress several genes involved in lipogenesis in both chow- and HFD-fed mice. In addition to SREBP-1c we identify PPARγ and CEBPα as novel FXR-regulated genes. We further show that FXR inhibits PPARγ expression by a mechanism requiring SHP whereas the inhibition of CEBPα or SREBP-1c by FXR is independent of SHP. Importantly, we demonstrate that INT-767 inhibits hepatic lipogenesis via activation of FXR. These novel data, together with previous observations [1], [40], indicate that activation of FXR inhibits lipogenesis likely via repressing PPARγ and/or CEBPα. The finding that INT-767 does not affect VLDL secretion or FAO (as determined by unchanged plasma β-HB levels) suggests that INT-767 improves liver steatosis likely via inhibition of hepatic lipogenesis. We have previously shown that activation of FXR induces hepatic SR-BI expression and increases reverse cholesterol transport [37], [41]. FXR activation is also reported to inhibit platelet activation in vitro [42]. Consistent with these observations, INT-767 induces hepatic SR-BI expression and inhibits or reverses the development of atherosclerosis in Apoe−/− mice. INT-767 markedly reduces VLDL-TG levels in Apoe−/− mice, at least partly due to induction of ApoC-II. Other mechanism(s) may also be involved in the hypolipidemic effect of INT-767. For instance, INT-767 may inhibit fat absorption via suppressing bile acid production. On the other hand, TGR5 activation has been shown to inhibit macrophage inflammation [16]. Indeed, we find that INT-767 inhibits monocyte/macrophage infiltration and oxidative stress in atherosclerotic lesions. Thus, INT-767 inhibits or reverses the development of atherosclerosis likely by improving hyperlipidemia, promoting RCT, and suppressing macrophage inflammation. In addition to regulating lipid homeostasis, our data show that INT-767 reduces obesity and improves energy expenditure. Previous studies show that activation of TGR5 improves energy homeostasis by inducing thermogenic genes in BAT [15]. In contrast, activation of FXR is shown to increase diet-induced obesity [17] whereas loss of FXR prevents diet-induced or genetic obesity [30]. Interestingly, our data suggest that INT-767 reduces obesity via activation of both TGR5 and FXR. Nonetheless, we realize that both Fxr−/− mice [30] and Tgr5−/− mice [43] are resistant to diet-induced obesity to some degrees, which makes the use of these two animal models imperfect for interpreting the results. It is unclear why FXR activation is also involved in INT-767-mediated alleviation of obesity. One possibility is that FXR activation is known to induce hepatic expression of FGF21 [44], a well-characterized inducer of thermogenesis. Despite its anti-obesity effect, INT-767 fails to reverse diet-induced glucose intolerance or insulin insensitivity, suggesting that INT-767 may not be useful for treatment of type II diabetes.