Impairment of PGC-1 Alpha Up-Regulation Enhances Nitrosative Stress in the Liver during Acute Pancreatitis in Obese Mice

• Main Authors: Sergio Rius-Pérez, Isabel Torres-Cuevas, María Monsalve, Francisco J. Miranda, Salvador Pérez
• Format: Article
• Language: English
• Published: MDPI AG 2020-09-01
• Series: Antioxidants
• Subjects: acute pancreatitis; obesity; nitrosative stress; PGC-1α; liver
• Online Access: https://www.mdpi.com/2076-3921/9/9/887

Acute pancreatitis is an inflammatory process of the pancreatic tissue that often leads to distant organ dysfunction. Although liver injury is uncommon in acute pancreatitis, obesity is a risk factor for the development of hepatic complications. The aim of this work was to evaluate the role of PGC-1α in inflammatory response regulation in the liver and its contribution to the detrimental effect of obesity on the liver during acute pancreatitis. For this purpose, we induced acute pancreatitis by cerulein in not only wild-type (WT) and PGC-1α knockout (KO) mice, but also in lean and obese mice. PGC-1α levels were up-regulated in the mice livers with pancreatitis. The increased PGC-1α levels were bound to p65 to restrain its transcriptional activity toward <i>Nos2</i>. Lack of PGC-1α favored the assembly of the p65/phospho-STAT3 complex, which promoted <i>Nos2</i> expression during acute pancreatitis. The increased transcript <i>Nos2</i> levels and the pro-oxidant liver status caused by the down-regulated expression of the PGC-1α-dependent antioxidant genes enhanced nitrosative stress and decreased energy charge in the livers of the PGC-1α KO mice with pancreatitis. It is noteworthy that the PGC-1α levels lowered in the obese mice livers, which increased the <i>Nos2</i> mRNA expression and protein nitration levels and decreased energy charge during pancreatitis. In conclusion, obesity impairs PGC-1α up-regulation in the liver to cause nitrosative stress during acute pancreatitis.