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

ABSTRACT: 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-1? 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-1? knockout (KO) mice, but also in lean and obese mice. PGC-1? levels were up-regulated in the mice livers with pancreatitis. The increased PGC-1? levels were bound to p65 to restrain its transcriptional activity toward Nos2. Lack of PGC-1? favored the assembly of the p65/phospho-STAT3 complex, which promoted Nos2 expression during acute pancreatitis. The increased transcript Nos2 levels and the pro-oxidant liver status caused by the down-regulated expression of the PGC-1?-dependent antioxidant genes enhanced nitrosative stress and decreased energy charge in the livers of the PGC-1? KO mice with pancreatitis. It is noteworthy that the PGC-1? levels lowered in the obese mice livers, which increased the Nos2 mRNA expression and protein nitration levels and decreased energy charge during pancreatitis. In conclusion, obesity impairs PGC-1? up-regulation in the liver to cause nitrosative stress during acute pancreatitis.

SUBMITTER: Rius-Perez S

PROVIDER: S-EPMC7554866 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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

Rius-Pérez Sergio S Torres-Cuevas Isabel I Monsalve María M Miranda Francisco J FJ Pérez Salvador S

Antioxidants (Basel, Switzerland) 20200919 9

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 ...[more]

PMID: 32961723

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Project description:Redox-based signaling is fundamental to the capacity of bacteria to sense, and respond to, nitrosative and oxidative stress encountered in natural and host environments. The conserved RNA polymerase regulatory protein DksA is a thiol-based sensor of reactive nitrogen and oxygen species. DksA-dependent transcriptional control promotes antinitrosative and antioxidative defenses that contribute to Salmonella pathogenesis. The specific adaptive changes mediated by DksA in response to reactive species, however, have not been elucidated. Herein, we characterize DksA-dependent changes in gene expression in Salmonella enterica experiencing nitrosative stress. Genome-wide expression analysis of wild-type and ?dksA Salmonella exposed to the nitric oxide ((•)NO) donor DETA NONOate demonstrated (•)NO- and DksA-dependent regulatory control of 427 target genes. Transcriptional changes centered primarily on genes encoding aspects of cellular metabolism. Several antioxidants and oxidoreductases important in redox buffering, (•)NO detoxification, and damage repair were also observed to be up-regulated in an (•)NO- and DksA-dependent manner. Compared to wild-type bacteria, (•)NO-treated ?dksA Salmonella exhibited a de-repression of genes encoding components of iron homeostasis and failed to activate sulfur assimilation and cysteine biosynthetic operons. As cysteine is integral to efficient antinitrosative and antioxidative defense and repair programs, we further examined the redox-responsive transcriptional control of cysteine biosynthesis by DksA. These investigations revealed that the activation of genes comprising cysteine biosynthesis also occurs in response to hydrogen peroxide, is dependent upon the redox-sensing zinc finger motif of DksA, and requires the transcriptional regulator CysB. Our observations demonstrate that DksA mediates global adaptation to nitrosative stress in Salmonella and provide unique insight into a novel regulatory mechanism by which cysteine biosynthesis is controlled in response to reactive oxygen and nitrogen species.

Dataset Information

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

Publications

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

Similar Datasets

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