Regulation of the hedgehog pathway by the ketogenic diet with radiation exposure

Abstract

Hedgehog signaling is a pathway that directs morphogenesis during embryonic development. In adult healthy liver, Hedgehog signaling is inactive. It, however, becomes drastically reactivated upon liver injury. This pathway is responsible for regulating cell differentiation by promoting proliferative activities in multiple liver cells including hepatocytes and progenitor cells. Activation of Hedgehog signaling is implicated in clinical pathology of many liver diseases including liver fibrosis, alcoholic and non-alcoholic liver diseases, and liver cancers. Radiation can induce oxidative stress which causes serious cell damage; the hedgehog pathway typically is activated when the liver is exposed to radiation. Related, the ketogenic diet lowers the prevalence of inflammation response by mitigating the effects of oxidative stress. Therefore, the main goal of this study is to understand how the ketogenic diet influences inflammation response when the subject is exposed to radiation. The hypothesis of this study is that inflammatory response can be modified through the Hedgehog pathway and influence inflammatory status of liver. Since the ketogenic diet may alleviate any damage caused by the radiation treatment, we will be reviewing how much damage has occurred, if any, by examining the prevalence of the Hedgehog pathway. In this study, 5weekold mice were either treated with control diet (10% fat, no radiation), control diet and radiation treatment, or ketogenic diet (60% fat) and radiation. Radiation treatment started at 13 weeks of age, and mice are sacrificed and analyzed at 18 weeks. Critical genes involved in hedgehog signaling, Cdh2, Gli2, Tgfb1, Ihh, Col1a1, Ctnnb1 and cMyc, were analyzed in the mouse liver. Compared to animals fed with control diet before radiation, animals fed with ketogenic diet after radiation have significantly increased mRNA expression of Cdh2 and Tgfb1 (P<0.05), while animals fed with control diet after radiation remain unchanged. On the other hand, compared to animals fed with control diet before radiation, animals fed with ketogenic diet after radiation have significantly decreased mRNA expression of Gli2, Ihh and Col1a1(P<0.05), while animals fed with control diet after radiation remain unchanged. In addition, mRNA expression of cMyc was found to be significantly increased (P<0.05) in animals fed with control diet after radiation, while animals fed with ketogenic diet after radiation remain unchanged comparing to animals fed with control diet before radiation. These preliminary data suggest that ketogenic diet may affect the responses triggered by radiation exposure by hedgehog pathway in liver, however, further investigation is required to fully understand the mechanism of how the hedgehog pathway is regulated by the ketogenic diet. Support or Funding Information This project was supported by UIUC Research Board grant #12192, the USDA Cooperative State Research, Education and Extension Service, Hatch project numbers # ILLU-698-923 and ILLU-698-369, ILLU-698-391, and the Data Purchase Program from the University of Illinois Library. Animals fed with the ketogenic diet after radiation have significantly increased mRNA expression of the Cdh2 gene. Animals fed with the control diet after radiation have no significant change in mRNA expression. Animals fed with the ketogenic diet after radiation have significantly increased mRNA expression of the Tgfb1 gene. Animals fed with the control diet after radiation have no significant change in mRNA expression. There is decreased mRNA expression of the Gli2 gene among animals fed with the ketogenic diet after radiation. The mRNA expression in animals fed with the control diet after radiation remains unchanged. There is decreased mRNA expression of the Ihh gene among animals fed with the ketogenic diet after radiation. The mRNA expression in animals fed with the control diet after radiation remains unchanged. There is decreased mRNA expression of the Col1a1 gene among animals fed with the ketogenic diet after radiation. The mRNA expression in animals fed with the control diet after radiation remains unchanged. The mRNA expxression of the cMyc gene was significantly increased in animals fed with the control diet after radiation. Animals fed with the ketogenic diet after radiation did not show a change in mRNA expression when compared with the animals fed with the control diet before radiation. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.