Abstract
Bile acid signaling is a critical regulator of glucose and energy metabolism, mainly through the nuclear receptor FXR and the G protein-coupled receptor TGR. The purpose of the present study was to investigate whether dual activation of FXR and TGR5 plays a significant role in the prevention of atherosclerosis progression. To evaluate the effects of bile acid signaling in atherogenesis, ApoE−/− mice and LDLR−/− mice were treated with an FXR/TGR5 dual agonist (INT-767). INT-767 treatment drastically reduced serum cholesterol levels. INT-767 treatment significantly reduced atherosclerotic plaque formation in both ApoE−/− and LDLR−/− mice. INT-767 decreased the expression of pro-inflammatory cytokines and chemokines in the aortas of ApoE−/− mice through the inactivation of NF-κB. In addition, J774 macrophages treated with INT-767 had significantly lower levels of active NF-κB, resulting in cytokine production in response to LPS through a PKA dependent mechanism. This study demonstrates that concurrent activation of FXR and TGR5 attenuates atherosclerosis by reducing both circulating lipids and inflammation.
Highlights
In addition to their role in the formation of intestinal micelles, bile acids serve as signaling molecules through two major receptors, Farnesoid X Receptor (FXR) and TGR5
A number of reports suggest that activation of bile acid signaling pathways can prevent or lessen both dyslipidemia and inflammation through two bile acid receptors, FXR and TGR5 [4,8,25]
We demonstrate that a novel FXR and TGR5 dual agonist, INT-767, potently inhibits atherosclerotic formation by preventing hyperlipidemia and inhibiting pro-inflammatory cytokine production in macrophages
Summary
In addition to their role in the formation of intestinal micelles, bile acids serve as signaling molecules through two major receptors, Farnesoid X Receptor (FXR) and TGR5. FXR is a nuclear receptor that is activated by bile acids such as chenodeoxycholic acid [1,2,3]. TGR5 ( designated as GPBAR1 or M-BAR) is a Gprotein coupled bile acid receptor highly expressed in the intestine and gallbladder [8,9]. TGR5 is abundantly expressed in CD14-positive monocytes and macrophages, where its activation mediates immunosuppressive effects [8]. TGR5 activation by bile acids in monocytes, alveolar macrophages and Kupffer cells attenuates phagocytosis and cytokine production in response to lipopolysaccharides (LPS) in a cAMP-dependent manner [8,13,14,15]. A recent study showed that pharmacological activation of TGR5 elicits anti-atherogenic effects by reducing macrophage inflammation and lipid uptake [13]
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