Statins Prevent Pancreatic Diseases Through Mitophagy Activation
Abstract
This proposal, addressing the topic area Pancreatitis, is designed to determine the mechanisms of statin (an agent used to lower blood cholesterol) mediating protection from pancreatitis, an observation recently reported using a retrospective cohort analysis of large clinical datasets. Pancreatitis often occurs in a continuum starting with one episode of acute pancreatitis, progressing in some patients to recurrent episodes of acute pancreatitis and chronic pancreatitis. Further, chronic pancreatitis has a very high risk for progression to pancreatic cancer, the most lethal of human cancers. There are no effective treatments for pancreatitis, so the observation that statin use is associated with reduced risk of pancreatitis creates a very real possibility that the continuum of these severe pancreatic diseases can be prevented. Thus, this clinical observation presents an unprecedented opportunity to find options to prevent these serious and life-threatening disorders. This project is designed to determine the mechanism of effects of statins, which, we predict, will provide a set of options for prevention of the pancreatic disorders that can be confirmed with preclinical testing, which will lead to important clinical testing. How statins could have beneficial effects in the pancreatic diseases is unknown. In order to approach the mechanisms involved, we use a combination of recent findings in myocardial cells showing that statins promote a robust and stress-resistant population of mitochondria by enhancing the removal of older and stress-damaged mitochondria through autophagy, the cell s mechanism of engulfing and removing old and non-functional cell components. In the case of removing mitochondria, the process is called mitophagy. In the pancreas, mitochondrial failure is the key mechanism initiating pancreatitis, and this failure can be prevented by a signal coming from the endoplasmic reticulum called spliced X box protein-1 (sXBP1), which also promotes autophagy. Considering these findings, we created an innovative hypothesis stating that statins prevent a continuum of exocrine pancreatic pathologies initiated in the acinar cell by enhancing a mitochondrial population resistant to failure when faced with pancreatitis-inducing stresses. We propose that this statin effect is due to their ability to promote resistant mitochondria via sXBP-1 upregulation of autophagy machinery combined with mechanisms to target damaged mitochondria to the autophagic machinery. To test the hypothesis, we propose aims that are designed to determine the effects of simvastatin (the most commonly used statin) treatment in vitro and in vivo on expression of sXBP1 and pathways of mitophagy in acinar cells of the pancreas using rodents as well as acinar cells from humans. We then will specifically evaluate the effect of the simvastatin treatment on the ability of mitochondria to resistant stresses that cause their failure. Finally, we will perform experiments to prove the role of sXBP1 and trafficking molecules that help move the mitochondria to the autophagy destination through methods of inhibition of these processes. Our expected findings are that simvastatin will promote mitophagy involving the sXBP1 pathway, resulting in a mitochondrial population resistant to failure, thus preventing pancreatitis. The results of the studies will also allow us to hypothesize and pursue further in-depth studies supported by sustainable granting mechanisms. The innovation of this project lies in the fact that determining the role of mitophagy in the mechanisms of physiology and disease is a novel concept in the pancreatic field. Further, demonstrating the effects of simvastatin on pathways from the endoplasmic reticulum (i.e., sXBP1) and mitophagy is novel in the pancreatic field. Our innovative and cross-disciplinary approach has the possibility of developing a new paradigm in the field of pancreatology that will lead to pr
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710138
Entities
People
- Stephen J Pandol
Organizations
- Cedars-Sinai Medical Center
- United States Army