Peroxisome proliferator-activated receptor γ (PPARγ) and sepsis

Abstract

This review describes the role of the nuclear hormone receptor PPARgamma as a double-edged sword in sepsis. On the one hand, PPARgamma inhibits pro-inflammatory gene expression, predominantly by scavenging transcription factors and their cofactors, thus preventing them from binding to their cognate binding sites in the promoters of target genes. The expressions of the affected genes, such as those for inducible nitric oxide synthase, TNF-alpha, or IL-1beta, are repressed. Therefore, PPARgamma is suggested to be beneficial in hyper-inflammatory diseases, such as sepsis. In animal models of sepsis, PPARgamma agonist pretreatment auspiciously attenuated inflammation compared with control animals, accompanied by their improved survival rate. On the other hand, PPARgamma provokes apoptosis, which in the hyper-inflammatory phase of sepsis might be helpful because the number of immune cells, such as monocytes, macrophages, and neutrophils, involved in secreting high amounts of proinflammatory mediators will be reduced. In contrast, during the anti-inflammatory phase, cell death of immune cells, especially of T lymphocytes, is supposed to be deleterious. Under these circumstances, a second infection cannot be adequately answered, thus causing septic shock and multi-organ dysfunction syndrome. Therefore the role of PPARgamma is still ambiguous. Particularly its role in initiating apoptosis awaits further clarification to finally elucidate its impact on sepsis development.

25-Hydroxycholesterol-3-sulfate attenuates inflammatory response via PPARγ signaling in human THP-1 macrophages

“…APR increases plasma triglyceride levels, de novo hepatic fatty acid synthesis, and suppression of fatty acid oxidation (34). The molecular mechanism during the APR involves coordinated changes in several orphan nuclear receptors, including PPARs, LXRs, and RXRs (34,57). PPAR␥ as well as LXRs reciprocally regulate inflammation and lipid metabolism (4,10).…”

Glycogen synthase kinase-3β regulates anti-inflammatory property of fluoxetine

“…LPS down-regulates the expression and activity of PPARγ, which participates in hyper-inflammatory diseases, such as sepsis [16]. Apart from enhancement of PPARγ activity, a putative GSK-3β inhibitor NP031115 has been reported to have an antidepressant-like effect in mice, which is similar to the effects of fluoxetine [43].…”

“…Reactive oxygen species (ROS) not only is involved in inflammatory responses, but also is a secondary messenger in intracellular signal transduction and regulates the actions of several signaling pathways [10,15]. These inflammatory events, at least in part, were associated with reduced expression and activity of peroxisome proliferator-activated receptor γ (PPARγ) [16,17]. However, little is known about the anti-inflammatory effects of fluoxetine through the above signal pathways.…”

The Role of Altered Lipid Metabolism in Septic Myocardial Dysfunction

“…Adipocytes are the only cells able to hydrolize TG giving rise to FFA and glycerol utilized by other tissues. This process is initiated by the adipose triglyceride lipase (ATGL) catalysing the hydrolysis of triglycerides to diglycerides followed by the hydrolysis of diglycerides to monoglycerides by the hormone-sensitive lipase (HSL) able also to catalyse the first phase and of monoglycerides to TG and glycerol by the monoglyceride lipase (MGL) [81][82][83]. ATGL deficiency is associated with fat deposition in all tissues indicating that ATGL is rate limiting in the catabolism of cellular fat depots [84].…”