Obesity causes PGC‐1α deficiency in the pancreas leading to marked IL‐6 upregulation via NF‐κB in acute pancreatitis

Abstract

Obesity is associated with local and systemic complications in acute pancreatitis. PPARγ co-activator 1α (PGC-1α) is a transcriptional co-activator and master regulator of mitochondrial biogenesis that exhibits dysregulation in obese subjects. Our aims were 1) to study PGC-1α levels in pancreas from lean or obese rats and mice with acute pancreatitis; and 2) to determine the role of PGC-1α in the inflammatory response during acute pancreatitis elucidating the signaling pathways regulated by PGC-1α. Lean and obese Zucker rats and lean and obese C57BL6 mice were used first, and subsequently wild-type and PGC-1α knock-out (KO) mice with cerulein-induced pancreatitis were used to assess the inflammatory response and expression of target genes. Ppargc1a mRNA and protein levels were markedly down-regulated in pancreas of obese mice versus lean mice. PGC-1α protein levels increased in pancreas of lean mice with acute pancreatitis, but not in obese mice with pancreatitis. Il6 mRNA levels were dramatically up-regulated in pancreas of PGC-1α KO mice after cerulein-induced pancreatitis in comparison with wild type mice with pancreatitis. Edema and the inflammatory infiltrate were more intense in pancreas from PGC-1α KO mice than in wild type mice. The lack of PGC-1α markedly enhanced nuclear translocation of phospho-p65 and recruitment of p65 to Il6 promoter. PGC-1α bound phospho-p65 in pancreas during pancreatitis in wild type mice. Glutathione depletion in cerulein-induced pancreatitis was more severe in KO mice than in wild type mice. PGC-1α KO mice with pancreatitis, but not wild type mice, exhibited increased MPO activity in the lungs together with alveolar wall thickening and collapse, which were abrogated by blockade of the IL-6 receptor gp130 with LMT-28. In conclusion, obese rodents exhibit PGC-1α deficiency in the pancreas. PGC-1α acts as selective repressor of NF-κB towards IL-6 in pancreas. PGC-1α deficiency markedly enhanced NF-κB-mediated up-regulation of Il6 in pancreas in pancreatitis, leading to severe inflammatory response.

PGC-1α, Inflammation, and Oxidative Stress: An Integrative View in Metabolism

“…Recently, we found that severity of acute pancreatitis in obese mice is associated with PGC-1α levels. Thus, mice lacking PGC-1α exhibited increased levels of inflammatory infiltrate in the pancreas with pancreatitis [5]. It has been previously reported that the severity of sepsis-associated acute kidney injury (AKI) correlates with PGC-1α levels in the kidney, and accordingly, lack of PGC-1α causes persistent kidney injury following endotoxemia [128].…”

“…PGC-1α is positively upregulated when cells are exposed to oxidative stress in order to prevent oxidative damage [83]. Accordingly, the lack of PGC1α is associated with a higher susceptibility to oxidative damage in mice [5,61,84]. Interestingly, even PGC-1α heterozygote (PGC-1α (+/-)) mice failed to augment Sod2 mRNA and protein levels in liver after peritonitis induction, which led to increased levels of mitochondrial oxidized glutathione (GSSG)/reduced glutathione (GSH) ratio and protein carbonyls in these mice [85].…”

“…In addition to its role in adaptive thermogenesis, PGC-1α is presently described as a master regulator of mitochondrial biogenesis and function, including oxidative phosphorylation (OXPHOS) and reactive oxygen species (ROS) detoxification [2]. In recent years, PGC-1α has been associated with many inflammatory and meta-bolic diseases, and its crucial role regulating mitochondrial function, oxidative stress, and metabolic pathways in diverse tissues has been revealed [3][4][5][6]. We herein review the different functions and molecular pathways regulated by PGC-1α, which connect oxidative stress and mitochondrial metabolism with inflammatory response and metabolic syndrome.…”

Perivascular adipose tissue–derived extracellular vesicle miR‐221‐3p mediates vascular remodeling

“…Up-regulation of PGC-1a mitigates these parameters and can reduce atherosclerotic lesions (65)(66)(67)(68)(69). PGC-1a is readily induced by exercise (70) and caloric restriction (71); in contrast, it is down-regulated by obesity (72). miR-221-3p, along with miR-19b-3p and miR-222-3p, located in the intima of atherosclerotic vessels, could posttranscriptionally regulate PGC-1a protein expression, exerting their roles in the pathogenesis of atherosclerosis by modulating endothelial cell apoptosis (41).…”

New wine into old wineskins: PGC‐1α and NF‐κB in obesity and acute pancreatitis

“…Obesity, being a proinflammatory condition, potentiates inflammation in AP, but the exact mechanism mediating this effect has not been described. In a recent issue of The Journal of Pathology , Pérez and Ruiz‐Pérez et al connected obesity and AP through the transcriptional coactivator PPARγ coactivator 1α (PGC‐1α), a master regulator of metabolic and oxidative homeostasis.…”