Inhibition of lipogenesis reduces inflammation and organ injury in sepsis.

Abstract

BACKGROUND:

Sepsis is a life-threatening acute inflammatory condition associated with metabolic complications. Accumulation of free fatty acids (FFAs) induces inflammation and causes lipotoxic effects in the liver. Because fatty acid metabolism plays a role in the inflammatory response, we hypothesized that the administration of C75, a fatty acid synthase inhibitor, could alleviate the injury caused by sepsis.

METHODS:

Male mice were subjected to sepsis by cecal ligation and puncture (CLP). At 4 h after CLP, different doses of C75 (1- or 5-mg/kg body weight) or vehicle (20% dimethyl sulfoxide in saline) were injected intraperitoneally. Blood and liver tissues were collected at 24 h after CLP.

RESULTS:

C75 treatment with 1- and 5-mg/kg body weight significantly lowered FFA levels in the liver after CLP by 28% and 53%, respectively. Administration of C75 dose dependently reduced serum indexes of organ injury (aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase) and serum levels of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6). In the liver, C75 treatment reduced inflammation (TNF-α and IL-6) and oxidative stress (inducible nitric oxide synthase and cyclooxygenase 2) in a dose-dependent manner. The 5-mg dose improved the 10-d survival rate to 85% from that of 55% in the vehicle. In the presence of C75, TNF-α release in RAW 246.7 cells with 4-h lipopolysaccharide stimulation was also significantly reduced.

CONCLUSIONS:

C75 effectively lowered FFA accumulation in the liver, which was associated with inhibition of inflammation and organ injury as well as improvement in survival rate after CLP. Thus, inhibition of FFA by C75 could ameliorate the hepatic dysfunction seen in sepsis.

• Authors: Juan Pablo Idrovo, Weng-Lang Yang, Asha Jacob, Lana Corbo, Jeffrey Nicastro, Gene F Coppa, Ping Wang
• Journal: The Journal of surgical research (J Surg Res) Vol. 200 Issue 1 Pg. 242-9 (Jan 2016) ISSN: 1095-8673 [Electronic] United States
• PMID: 26216747 (Publication Type: Evaluation Study, Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• 4-methylene-2-octyl-5-oxofuran-3-carboxylic acid
• Biomarkers
• Enzyme Inhibitors
• 4-Butyrolactone

Topics

• 4-Butyrolactone (analogs & derivatives, pharmacology, therapeutic use)
• Animals
• Biomarkers (metabolism)
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Hepatic Insufficiency (etiology, metabolism, prevention & control)
• Inflammation (etiology, metabolism, prevention & control)
• Lipogenesis (drug effects)
• Liver (drug effects, metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Sepsis (complications, drug therapy, metabolism)
• Treatment Outcome