Fig 1: Proposed model of bile acid stimulated secretion of appetite and metabolism regulating hormones. (1) Food intake, and in particular fat consumption, stimulates the secretion of bile acids into the upper small intestine by CCK-mediated contraction of the gallbladder. (2) In addition to their well-known role in facilitating fat absorption (by micelle formation) bile acids activate TGR5 receptors which are located at the basolateral membranes of the enterocytes and therefore are activated secondary to bile acid (BA) absorption. Upon activation, the secretion of GIP, GLP-1, NT, and PYY is stimulated. Conjugated bile acids are absorbed through the secondary active transporter ileal-bile acid transporter (IBAT) which is predominantly expressed in the lower part of the small intestine, whereas unconjugated bile acids (which are more lipophilic) spontaneously cross the intestinal mucosal layer. (3) Eliminating bile acid absorption by BA-sequestrants (which cross bind both conjugated and unconjugated BAs into large unabsorbable complexes) or by direct IBAT inhibition (which attenuates the absorption of conjugated BAs) therefore eliminates BA-stimulated gut hormone secretion. (4) Collectively, the absorption mechanisms results in a very efficient BA absorption so about 95% of the secreted bile acids are returned to the liver through the enterohepatic circulation. (5) The majority of the returned bile acids are extracted by the liver (where they are reconjugated and rehydroxylated, allowing the same pool of bile acids to be secreted several times during the day), (6) Only 3–10% pass the liver and eventually ends up in the systemic circulation, (7) The pool is further diluted with a factor of about three since the hepatic return constitutes about 1/3 of the total venous return. (8) Therefore, only a small fraction of the secreted bile acid makes it to the systemic circulation.
Fig 2: The mediated effect of IL-6 and the STAT3/Akt/GSK3β/β-catenin pathway in the inhibiting effect of PANDER on GLP-1. After PANDER overexpression, STC-1 cells exhibited a decrease in the phosphorylation of STAT3/Akt/GSK3β, and the expression of β-catenin (Western blot, A–E). The exogenous addition of IL-6 reversed the activation of the STAT3/Akt/GSK3β/β-catenin pathway (Western blot, F–J) and restored the expression of GLP-1 protein in the PANDER-overexpressing group (immunofluorescence, P, Q). In contrast, after PANDER knockdown, STC-1 cells exhibited an increase in the phosphorylation of STAT3/Akt/GSK3β, and the expression of β-catenin (Western blot, K–O). The exogenous addition of the STAT3-specific inhibitor AG490 inhibited the activation of the STAT3/Akt/GSK3β/β-catenin pathway (Western blot, K–O) and the expression of GLP-1 protein in the PANDER-knockdown group (immunofluorescence, R, S). The scale of the immunofluorescence image is 1 cm : 20μ m. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.001.
Fig 3: Treatment with GLP-1 receptor antagonist (Exendin-9) worsens glucose tolerance test of placebo but not ibuprofen-treated mice. Glucose tolerance test (GTT) expressed in (mg/dL) in C57Bc/6J mice and treated with placebo vs. ibuprofen for two weeks, followed by the administration of 5 µg of Exendin-9 IP or normal saline 30 min before the experiment: n = 5 (Placebo + NS), 5 (Placebo + Ex-9), 6 (ibuprofen + NS), and 6 (ibuprofen + Ex-9). All results are presented as mean ± SEM (error bars) (n = 5–6). One-way ANOVA was used to detect differences between control and the three experimental groups. Statistical significances are denoted with asterisks as follows:; **, p ≤ 0.01.
Fig 4: The distribution of GLP-1 in aortic valves with or without calcification. Human aortic valves with calcification (n = 11) that underwent valve replacement operation and without calcification (n = 12) undergoing heart transplantation were assessed by histological and immunochemical analysis. (A) Sections were stained with hematoxylin and eosin, Alizarin Red S, and Masson trichrome staining. IHC stains of GLP-1 and counterstained with hematoxylin. The results of the Non-CAVD valves (left line) are shown at 100 × magnification, and the results of CAVD (right line) are shown at 20 × magnification. (B) The concentration of GLP-1 detected by IHC was determined by assessing its staining with Image-Pro Plus 6.0. The results are shown as the integrated optical density (IOD)/area. The Non-CAVD (n = 12) and CAVD valves (n = 11) are representative of three independent experiments, and five different fields in each section were detected (the P-value was control valves compared with CAVD).
Fig 5: GLP-1 Immunoreactivity in diabetic, control, and sham groups. Arrows show GLP-1 immunoreactivity. Bars: 20 μm
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