Good morning, everyone. Thank you for coming to our specific SIG session. So my job today is try to give a just brief overview for the biacid receptor. can be viewed as a seromolecules. So if you are looking at the structures of the biase. primary biacid. So this is structure. So as we know, biacid is end product of the cluster. So they converted from cluster, and then they can form either colic acid or chenodeoxycholic acid. So on the most conditions, these primary biacid, they are either conjugated by glycine or the taurine, so which we call conjugated biacid. So when they go into the gut and the microbiome, So for the biacid synthesis, we have already identified two specific pathways. So one we call the classical pathway. As you see here, there's one rate-limited enzyme, CYP. In addition to that, we have another pathway which called alternative pathway. So the rate-limited enzyme for this pathway is CYP27A1. It's happening in the mitochondria. So this enzyme, they also involved in the synthesized to the CDCA. So all these pathway has been identified and this is very simplified version. A lot of specific enzyme which is involved in the whole process in order to generate the biacid. And then in the gut, the bacteria which can further modify can convert these primary biacid first by deconjugation. So the major difference between humans and mice is that in mice, they have a myocardial acid. So in addition to that, in the gut, these mice primarily have a myocardial acid. As we know, the intra-hepatic circulation of the bio-acid is very important physiological process. So when we have, after every meal we eat, and we need this bio-acid, and go into the gut to help us to absorb all these lipid soluble nutritions. After this process, more than 95% of the bio-acid, they can be absorbed in the terminal ilia, and go back to the portal vein, and then return to the liver. So only 5% of the bio-acid, usually they lost every day, and these lost bio-acid will be replaced by de novo synthesize from the cholesterol. So any step which disrupt this intra-hepatic circulation, which can cause a different pathological disease. So for many years, the bio-acid was viewed as a detergent molecules. So which is very important, as I mentioned, for the nutrition absorption. Also it's very important for the antibiotic disposals. So however, during last two decade, bio-acid has been identified, a very important signaling molecules. So they are involved in the lipids, and the glucose, and the energy metabolism. So identification of the first nuclear receptor, specifically activated by bio-acid, FXR, is really expanded the field for the bio-acid research. So when we have access bio-acid, and it's going to activate these FXR in the nuclear, and the FXR, they can activate another downstream nuclear small protein shape, and which specifically can down-regulate CYP7A1. So this is very important pathway, which can maintain the homostasis of the bio-acid level. So, basically, the identification in this is first membrane receptor for biacid, so really expanded the field for the biacid research. So in addition to that, there's group also reported another G-protein couple receptor, the muscarin receptor, also involved in the biacid signaling in the muscle cells. And then about eight, seven years ago, our group identified that another receptor, sphingosine 1-phosphate receptor 2, which can activate, by the conjugate, the primary biacid in the hepatocytes. So by looking at all these three different receptors, they have very specific cell type location. For the TGR5, it's initially identified in the microphages. So really, identification of FXR is significantly expanded for the biacid research. Also in 1999, the three group, they simultaneously identified this receptor. So if you're looking at the PubMed, since 1999, so there are more than 2,400 publication is related to FXR has been published. Now also for specific receptors in the smooth muscle cells in the GI, this also has been noticed, but it's activated by the different metabolites of the biacid. So TGR5, which is very important regulators for the glucose and energy metabolism, and also things, identification of the TGR5 in 2002, there are more than 500 publication related to TGR5. So our group identified S1PR2, which also can be activated by the biacid, but it's mainly activated by the primary conjugated biacid. So we also found not only in the hepatocytes, they also found in the cholangiocytes. So this table just summarized a different type of receptor in the liver, different specific cells. So we noticed that here, hepatocytes, they have FXR, S1PR2, but no TGR5. And all other type of the liver cells, they all have all three receptors. And also if you're looking at the specificity for these different receptor, they are significant different. As noticed here, the FXR is mainly activated by the unconjugated biacid, and the TGR5 is by activated unconjugated, and the secondary biacid. But S1PR2 is mainly by the primary and the conjugated biacid. So the identification of FXR has been showed in the hepatocytes, a lot of different functions. I summarize here. So activation FXR in the hepatocytes, which can inhibit biacid synthesis, increase biacid secretion, and increase biacid conjugation, and also could increase glycogenesis. So FGF15 and FGF19, and then they can inhibit the glycolysis. So in the stellar cells, activation FXR, which can reduce the liver fibrosis. So in the intestine, actually, the biacid activation FXR, which can inhibit biacid uptake, and also can increase FGF15 and FGF19 secretion. So this is very important for the intestine functions. So in addition to that, in the L cells, activation FXR, which can reduce the GLP1 synthesis and the secretion. So TGR5, they are more involved in the immunocells, in the corpus cells, which can reduce the cytokine production, cholangiocytes, which can promote the cell proliferation, and then the increased secretion. However, in the hepatocytes, there's no TGR5. And in the intestine, and L cells, and activation TGR5, has been shown that it can increase GLP1 synthesis and the secretion. And also in EC cells, which also can downregulate the basal secretion, and also can reduce the signal induced by the chronological signals. And in addition to that, in the pancreatic alpha cells, has been shown that activation TGR5, which can increase the PC1 activity and promote the GLP1 generation. And also in the pancreatic beta cells, which can increase insulin secretion. So for the S1PR2 receptor, and then in the corpus cells, it also has been shown that they can reduce the cytokine production in the cholangiocytes, and can promote the cell proliferation, and also can increase the chloro and then bicarbonate secretion. So most importantly, in the hepatocytes, which can inhibit the biacid synthesis, increase ERK and AKT activation, and then also can induce the sphingosine kinase 1 activation, and increase fatty acid oxidation, specifically can inhibit histone acetylation. So we also found in the intestine epithelial cells, and S1PR2, which can specifically promote the epithelial cell proliferations. And in the recent study in the pancreas, also showed that they can promote progenitor survival, as well as ethanol and then endocrine specifications through the stabilization of the YAR pathway. So most recently, there's another group in Beijing University, they identified another specific S1P receptor activator, they can modulate the adipose tissue functions. So a recent study also has been shown that during the last two decades, a lot of effort in the pharmaceutical company, and then different research groups have shown that. So that specific target, FXR, TGR5, and S1PR2, has very important clinical potential to treat a different disease. So a lot of specific agonists for FXR and TGR5 has been developed, and some of them already in the clinical, on all the clinical trials. And also they have identified a specific antagonist for the FXR and the TGR5. So these specific chemicals and compounds, so they have the potential, but also they have a different specificity and the utilization in the clinical. I think you will hear a more detailed talk in the following lectures. So for S1PR2, there is no any specific agonist or antagonist has been used in the clinical trial, but some preclinical trial, the study has shown that if you specifically inhibit S1PR2, which can have a very important function to modulate the intestine function in the PSC animal models. So in the future, I think that understanding the cell-specific and tissue-specific function of individual bioacid receptor on the physiological and the pathological condition, which is very important. So in addition to that, to generate the mouse models with a humanized bioacid pool, so we continue a variable first step in clarifying the role of the bioacid and the receptor in different disease. And also, the long-term effect of the tissue-specific agonism or antagonism of the bioacid receptors still need to be assessed. So as we know, these bioacids, in addition to play a role in the pathological condition, they also play a very important role in the physiological condition. So any chemicals which can block this pathway also have some side effect. So this is, I think we need to keep in mind in the future, both basic and clinical studies. So I think that's all for my today's overview, I'd just like to thank all the funding. Thank you very much for your attention.

bioacids

receptors

cholesterol

lipid absorption

gut bacteria