1.Effects of gastric bypass surgery on serum total bile acid in obese diabetic patients and rats
Weili HE ; Hening ZHAI ; Geyang XU ; Jingge YANG ; Hua YANG ; Cunchuan WANG
Chinese Journal of Pathophysiology 2017;33(3):462-468
AIM:To observe the effects of gastric bypass surgery on the levels of serum total bile acid in the obese diabetic patients and rats .METHODS: Anthropometric data of obese diabetic patients with gastric bypass surgery from June 2011 to June 2016 were collected in the First Affiliated Hospital of Jinan University .Obese diabetic animal mo-del was established in SD rats by high-fat diet feeding combined with intraperitoneal injection of low-dose streptozocin .Gas-tric bypass surgery or sham operation was performed on the rats with successful modeling .The levels of serum total bile acid were measured by a Hitachi automatic biochemistry analyzer , and the content of hepatic cholesterol 7α-hydroxylase (CYP7A1) was detected by ELISA.The expression of hepatic CYP7A1 and small heterodimer partner (SHP) at mRNA and protein levels was determined by real-time PCR and Western blot, respectively.RESULTS:The serum levels of total bile acid were significantly increased in postoperative obese diabetic patients and rats as compared with control groups .Gas-tric bypass surgery inhibited rat hepatic CYP 7A1 content, mRNA level and protein level , but stimulated hepatic SHP ex-pression.CONCLUSION:Total serum bile acid increases in both patients and rats after gastric bypass surgery by non -typical bile acid synthesis pathway .
2.Interleukin-27 decreases ghrelin production through signal transducer and activator of transcription 3-mechanistic target of rapamycin signaling.
Heng ZHANG ; Qingjie LI ; Yuxin TENG ; Yubi LIN ; Shaojian LI ; Tingfeng QIN ; Linxi CHEN ; Jiana HUANG ; Hening ZHAI ; Quan YU ; Geyang XU
Acta Pharmaceutica Sinica B 2020;10(5):837-849
Interleukin-27 (IL-27), a heterodimeric cytokine, plays a protective role in diabetes. Ghrelin, a gastric hormone, provides a hunger signal to the central nervous system to stimulate food intake. The relationship between IL-27 and ghrelin is still unexplored. Here we investigated that signal transducer and activator of transcription 3 (STAT3)-mechanistic target of rapamycin (mTOR) signaling mediates the suppression of ghrelin induced by IL-27. Co-localization of interleukin 27 receptor subunit alpha (WSX-1) and ghrelin was observed in mouse and human gastric mucosa. Intracerebroventricular injection of IL-27 markedly suppressed ghrelin synthesis and secretion while stimulating STAT3-mTOR signaling in both C57BL/6J mice and high-fat diet-induced-obese mice. IL-27 inhibited the production of ghrelin in mHypoE-N42 cells. Inhibition of mTOR activity induced by siRNA or rapamycin blocked the suppression of ghrelin production induced by IL-27 in mHypoE-N42 cells. siRNA also abolished the inhibitory effect of IL-27 on ghrelin. IL-27 increased the interaction between STAT3 and mTOR in mHypoE-N42 cells. In conclusion, IL-27 suppresses ghrelin production through the STAT3-mTOR dependent mechanism.
3.Reactivation of PPARα alleviates myocardial lipid accumulation and cardiac dysfunction by improving fatty acid β-oxidation in Dsg2-deficient arrhythmogenic cardiomyopathy.
Yubi LIN ; Ruonan LIU ; Yanling HUANG ; Zhe YANG ; Jianzhong XIAN ; Jingmin HUANG ; Zirui QIU ; Xiufang LIN ; Mengzhen ZHANG ; Hui CHEN ; Huadong WANG ; Jiana HUANG ; Geyang XU
Acta Pharmaceutica Sinica B 2023;13(1):192-203
Arrhythmogenic cardiomyopathy (ACM), a fatal heart disease characterized by fibroadipocytic replacement of cardiac myocytes, accounts for 20% of sudden cardiac death and lacks effective treatment. It is often caused by mutations in desmosome proteins, with Desmoglein-2 (DSG2) mutations as a common etiology. However, the mechanism underlying the accumulation of fibrofatty in ACM remains unknown, which impedes the development of curative treatment. Here we investigated the fat accumulation and the underlying mechanism in a mouse model of ACM induced by cardiac-specific knockout of Dsg2 (CS-Dsg2 -/-). Heart failure and cardiac lipid accumulation were observed in CS-Dsg2 -/- mice. We demonstrated that these phenotypes were caused by decline of fatty acid (FA) β-oxidation resulted from impaired mammalian target of rapamycin (mTOR) signaling. Rapamycin worsened while overexpression of mTOR and 4EBP1 rescued the FA β-oxidation pathway in CS-Dsg2 -/- mice. Reactivation of PPARα by fenofibrate or AAV9-Pparα significantly alleviated the lipid accumulation and restored cardiac function. Our results suggest that impaired mTOR-4EBP1-PPARα-dependent FA β-oxidation contributes to myocardial lipid accumulation in ACM and PPARα may be a potential target for curative treatment of ACM.