GPBAR1/TGR5 mediates bile acid-induced cytokine expression in murine Kupffer cells.

GPBAR1/TGR5 is a novel plasma membrane-bound G protein-coupled bile acid (BA) receptor. BAs are known to induce the expression of inflammatory cytokines in the liver with unknown mechanism. Here we show that without other external stimuli, TGR5 activation alone induced the expression of interleukin 1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) in murine macrophage cell line RAW264.7 or murine Kupffer cells. The TGR5-mediated increase of pro-inflammatory cytokine expression was suppressed by JNK inhibition. Moreover, the induced pro-inflammatory cytokine expression in mouse liver by 1% cholic acid (CA) diet was blunted in JNK-/- mice. TGR5 activation by its ligands enhanced the phosphorylation levels, DNA-binding and trans-activities of c-Jun and ATF2 transcription factors. Finally, the induced pro-inflammatory cytokine expression in Kupffer cells by TGR5 activation correlated with the suppression of Cholesterol 7α-hydroxylase (Cyp7a1) expression in murine hepatocytes. These results suggest that TGR5 mediates the BA-induced pro-inflammatory cytokine production in murine Kupffer cells through JNK-dependent pathway. This novel role of TGR5 may correlate to the suppression of Cyp7a1 expression in hepatocytes and contribute to the delicate BA feedback regulation.

Berbamine inhibits the growth of liver cancer cells and cancer-initiating cells by targeting Ca²âº/calmodulin-dependent protein kinase II.

Liver cancer is the third leading cause of cancer deaths worldwide but no effective treatment toward liver cancer is available so far. Therefore, there is an unmet medical need to identify novel therapies to efficiently treat liver cancer and improve the prognosis of this disease. Here, we report that berbamine and one of its derivatives, bbd24, potently suppressed liver cancer cell proliferation and induced cancer cell death by targeting Ca(2+)/calmodulin-dependent protein kinase II (CAMKII). Furthermore, berbamine inhibited the in vivo tumorigenicity of liver cancer cells in NOD/SCID mice and downregulated the self-renewal abilities of liver cancer-initiating cells. Chemical inhibition or short hairpin RNA-mediated knockdown of CAMKII recapitulated the effects of berbamine, whereas overexpression of CAMKII promoted cancer cell proliferation and increased the resistance of liver cancer cells to berbamine treatments. Western blot analyses of human liver cancer specimens showed that CAMKII was hyperphosphorylated in liver tumors compared with the paired peritumor tissues, which supports a role of CAMKII in promoting human liver cancer progression and the potential clinical use of berbamine for liver cancer therapies. Our data suggest that berbamine and its derivatives are promising agents to suppress liver cancer growth by targeting CAMKII. Mol Cancer Ther; 12(10); 2067-77. ©2013 AACR.

Bile Acid Receptors and Liver Cancer.

Liver cancer, particularly hepatocellular carcinoma (HCC), is the third leading cause of cancer death in the world. Bile acids (BAs) are liver-produced amphipathic molecules that are required to facilitate the absorption of cholesterol, fat-soluble vitamins, and lipids in the intestine. However, BAs are also known to act as potential carcinogens and deregulation of BA homeostasis has been linked to HCC formation. Two key BA receptors, farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (TGR5), were recently identified, which provides great insights into BAs' normal physiological functions as well as their carcinogenic effects. In this review, we focus on the potential links among BAs, two BA receptors, and HCC. FXR and TGR5 not only play key roles in regulating BA homeostasis but also are essential in suppressing BAs' carcinogenic effects on liver cancer.