Zileuton prevents the activation of the leukotriene pathway and reduces sebaceous lipogenesis

Abstract

Arachidonic acid (AA) activates the 5-lipoxygenase, induces leukotriene-B 4 (LTB 4 ) synthesis, enhances interleukin-6 (IL-6) release and increases intracellular neutral lipids in human sebocytes. Moreover, the enzymes of LTB 4 biosynthesis are activated in acne-involved sebaceous glands. Zileuton a 5-lipoxygenase inhibitor, reduces the number of inflammatory acne lesions and lipogenesis in patients with acne. In this study, we investigated the activity of zileuton on LTB 4 generation, lipid content and IL-6 and -8 release from human SZ95 sebocytes in vitro. Pretreatment with zileuton partially prevented the AAinduced LTB 4 and IL-6 release and increased neutral lipid content. IL-6 release and neutral lipid content were also reduced under long-term zileuton treatment. In conclusion, zileuton prevents the activation of the leukotriene pathway and enhancement of lipogenesis by AA in human sebocytes in vitro.

The Kaposi's Sarcoma-Associated Herpesvirus (KSHV)-Induced 5-Lipoxygenase-Leukotriene B4 Cascade Plays Key Roles in KSHV Latency, Monocyte Recruitment, and Lipogenesis

“…5LO is an emerging target in obesity, insulin resistance, obesity-related fatty liver disease, metabolic dysfunction (118,119), and nonalcoholic fatty liver and nonalcoholic steatohepatitis (120). Since 5LO/LTB4 has been shown to induce lipogenesis in human sebocytes (121), breast cancer cells (60), and hepatitis B virus X protein-mediated development of hepatocellular carcinoma (122) and since 5LO inhibitors are known to directly downregulate lipogenesis in sebocytes (121) and hepatic steatosis (119), we hypothesized that KSHV infection induces the 5LO/LTB4 cascade to enhance lipogenesis (123,124) and favor latency. Our results show that LTB4 promotes FASN transcription and gene expression and silencing of 5LO effectively reduces the protein levels of FASN (Fig.…”

Beyond acne: Current aspects of sebaceous gland biology and function

“…However, the activity of PPAR agonists seems to be complex: PPARγ agonists have been shown to increase sebum production in adults with diabetes and hyperlipidemia [64]. In contrast, PPARα agonists seem to inhibit sebaceous lipogenesis [65] through prevention of the activation of the proinflammatory leukotriene pathway [66]. Moreover, PPAR agonists, especially that for PPARδ, exhibit anti-apoptotic activity on human sebocytes by inducing the activation of PKB/Akt and p44/42, two kinases involved in anti-apoptosis and proliferation, respectively and by suppressing histone-associated DNA fragments [67].…”

An update on the role of the sebaceous gland in the pathogenesis of acne

“…41 The involvement of 5-LOX in the pathogenesis of acne has led to new therapeutic strategies to deal with the disease. 83 Cytokines are present in normal sebaceous glands, and they are affected by many factors. IL-1α, TNFα, IL-6 and IL-8 are released into supernatant in unstressed sebocyte culture.…”