Deficient Endoplasmic Reticulum Acetyl-CoA Import in Pancreatic Acinar Cells Leads to Chronic Pancreatitis

Abstract

Pathologic activation of the unfolded protein response is a key event in the development of pancreatitis. Impairing the endoplasmic reticulum acetyl-CoA transporter AT-1 in acini leads to chronic overactivation of the unfolded protein response and presents a spontaneous chronic pancreatitis phenotype. BACKGROUND & AIMS: Maintaining endoplasmic reticulum (ER) proteostasis is essential for pancreatic acinar cell function. Under conditions of severe ER stress, activation of pathogenic unfolded protein response pathways plays a central role in the development and progression of pancreatitis. Less is known, however, of the consequence of perturbing ER-associated posttranslational protein modifications on pancreatic outcomes. Here, we examined the role of the ER acetyl-CoA transporter AT-1 on pancreatic homeostasis. METHODS: We used an AT-1 S113R/þ hypomorphic mouse model, and generated an inducible, acinar-specific, AT-1 knockout mouse model, and performed histologic and biochemical analyses to probe the effect of AT-1 loss on acinar cell physiology. RESULTS: We found that AT-1 expression is down-regulated significantly during both acute and chronic pancreatitis. Furthermore, acinar-specific deletion of AT-1 in acinar cells induces chronic ER stress marked by activation of both the spliced x-box binding protein 1 and protein kinase R-like ER kinase pathways, leading to spontaneous mild/moderate chronic pancreatitis evidenced by accumulation of intracellular trypsin, immune cell infiltration, and fibrosis. Induction of acute-on-chronic pancreatitis in the AT-1 model led to acinar cell loss and glad atrophy. CONCLUSIONS: These results indicate a key role for AT-1 in pancreatic acinar cell homeostasis, the unfolded protein response, and that perturbations in AT-1 function leads to pancreatic disease.

Pancreatic Acinar Cell Protein Synthesis, Intracellular Transport, and Export

“…glycosylated) proteins and promotes their entry into the secretory pathway, whereas improperly folded proteins cannot be acetylated appropriately and are thus subject to degradation. It has been recently shown that AT-1 expression increases at the onset of pancreatitis but falls as the disease progresses 16 . Furthermore, studies involving mice expressing mutant AT-1 S113R/+ , a human mutation associated with hereditary spastic paraplegias 17 , or pancreatic acinar-specific AT-1 deletion, show elevated ER stress, inflammation, and fibrosis consistent with a chronic pancreatitis-like phenotype, which unexpectedly includes enhanced trypsin activation 16 .…”

Protein Lysine Acetylation

“…The contribution by Cooley et al 1 should lead to additional studies. Confirming that AT-1 mRNA levels correspond to protein content and documenting that the responses are conserved in human acinar cells are important.…”

“…This makes it particularly susceptible to endoplasmic stress responses, a process that can contribute to the pathogenesis of pancreatitis and pancreatic cancer. The study by Cooley et al 1 in this issue of Cellular and Molecular Gastroenterology and Hepatology highlights how important acetylation of lysine resides on nascent proteins is to acinar function and its links to ER stress. Although the work is done in the context of pancreatic acinar cell responses, the findings likely have relevance to other gastrointestinal tissues.…”

“…Although described more than 50 years ago, the functional and cellular effects of protein acetylation on surface exposed lysine residues of nascent proteins has been much less studied and is the topic examined by Cooley et al. 1 …”

Pancreatic Digestive Enzyme Synthesis and its Translational Control

“…Several studies directed at finding different physiologic and metabolic imbalances in the exocrine pancreas, such as oxidative stress, mitochondrial dysfunction and autophagy, deregulation of ATP generation and ER Acetyl-CoA (AT) availability, changes in lipid metabolism, inflammatory and cell death responses (10,178), have demonstrated that these mechanisms often first manifest by abnormal cytosolic Ca 2+ signaling. After abnormal calcium cytosolic levels, there is a multifaceted set of organelles and cellular interactions that trigger ER stress in pancreatic acinar cells, leading the way to different degrees of cell damage (84) and, ultimately, to acute (63,65) and chronic (32) pancreatitis.…”