Carnitine Acetyltransferase and Metabolic Regulation in the Exocrine Pancreas

Duke University, Durham NC

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Linked publications & trials

Abstract

? DESCRIPTION (provided by applicant): Pancreatitis is a prevalent, costly, and potentially life-threatening clinical problem for which the pathophysiology is poorly understood and treatment options are extremely limited. This disease is characterized by acinar cell dysfunction leading to inappropriate activation of trypsin. A variety of pancreatitis models suggest that metabolic perturbations resulting in mitochondrial dysfunction and aberrant autophagy might play an early and central role in the pathophysiology of this disorder. Research in our laboratory centers on the interplay between mitochondrial dysfunction and metabolic disease. We recently discovered that a mitochondrial enzyme known as carnitine acetyltransferase (CrAT) is essential for acinar cell survival. Remarkably, conditional genetic ablation of CrAT in adult mice leads to rapid and massive acinar death with morphological changes consistent with pancreatitis. This finding raises the intriguing questions of why this event is so catastrophic in these cells, and do similar perturbations occur in the context of pancreatic disease? CrAT is a freely reversible enzyme that transfers two-carbon acetyl groups between CoA and L-carnitine, which permits shuttling of acetyl moieties between the mitochondria and other cellular compartments. Studies in skeletal muscle show that this shuttle system buffers metabolic transitions between states of high and low energy demand, and thereby maintains mitochondrial acetyl group balance while also modulating production of reactive oxygen species (ROS). This project aims to delineate the role of CrAT in acinar cell function using state-of-the-art metabolomics and molecular physiology approaches. Results from these studies could provide new and important clues to understanding the molecular basis of pancreatitis.