Effects of Di-(2-ethylhexyl) Phthalate on Lipid Metabolism by the JAK/STAT Pathway in Rats

Abstract

The most widely used plasticizer, di-(2-ethylhexyl) phthalate (DEHP), is known to affect lipid metabolism and adipogenesis. We studied the effects of dietary DEHP exposure on metabolism in rats as well as the role of the JAK/STAT pathway in this process. Eighty rats were exposed to DEHP (0, 5, 50 and 500 mg/kg/d) through dietary intake for 4 weeks. We then collected blood samples, liver, and adipose tissues to detect modifications in the levels of serum lipids, leptin, adiponectin and insulin. JAK3, STAT5a and PPARγ expression were detected at both the gene and protein levels. The activation of JAK3 and STAT5a was also detected. The DEHP-exposed rats had increased body weight, serum lipid, insulin, and leptin levels. Moreover, the JAK3/STAT5a pathway was activated in the adipose tissue; however, this pathway was not activated in the liver. The mRNA of SREBP-1c in the liver was increased significantly among each of the groups, in contrast to the levels found in the mature SREBP-1c protein form. Furthermore, the expression of FABP4, Acox and FASn was decreased in the liver, but increased in adipose tissue. Thus, we conclude that exposure to DEHP reduces the hydrolysis of lipid and promotes triglyceride accumulation by oppositely regulating the activation state of JAK/STAT pathway in the liver and adipose tissue, resulting in the disorder of body lipid metabolism and obesity.

METTL3 inhibits BMSC adipogenic differentiation by targeting the JAK1/STAT5/C/EBPβ pathway via an m 6 A‐YTHDF2–dependent manner

“…In most cases, JAKs depend on STATs to modulate physiologic processes (10)(11)(12)(13)(14); therefore, STAT proteins may also play important roles in the transcriptional control of adipogenesis (60). Studies in subcutaneous human primary adipocytes confirmed the up-regulation of STAT3 and STAT5 during differentiation (61).…”

“…The JAK/STAT pathway plays an important role in mediating cell fates, such as apoptosis, differentiation, and proliferation (10)(11)(12)(13)(14). The suppression of JAK/STAT signaling causes stochastic and ectopic neural stem cell differentiation in vivo, suggesting an evolutionarily conserved function of JAK/STAT to regulate the robustness of stem cell differentiation (57).…”

“…We next studied how JAK1 participated in pBMSC adipogenesis differentiation. In most cases, JAKs rely on STATs to modulate various physiologic processes including development and lipid metabolism progress (10)(11)(12)(13)(14). Immunoblot assays show that expression of phosphorylated (p)-STAT3 and p-STAT5 dramatically increased during pBMSC differentiation, whereas STAT3 and STAT5 exhibited no obvious difference (Fig.…”

“…Ultimately, these signaling networks regulate the expressions of critical transcription factors such as peroxisome proliferatoractivated receptor g2 (PPARg2) and CCAAT/enhancer binding proteins (C/EBPs) for adipogenesis, as well as runt-related transcription factor 2 and osterix for osteogenesis (9). Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway plays an important role in a variety of physiologic processes including development, hematopoiesis, inflammation, and lipid metabolism progress (10)(11)(12)(13)(14). The JAK family of receptor-associated tyrosine kinases act as primary transducers of multiple cytokine receptors and mediate a variety of their effects through the phosphorylation of the transcription factor STATs (12,(15)(16)(17)(18)(19).…”

Di (2‐ethylhexyl) phthalate targets the thioredoxin system and the oxidative branch of the pentose phosphate pathway in liver of Balb/c mice

“…Previous studies demonstrated that DEHP is hepatocarcinogen in rodent species and related this effect to the peroxisome proliferator activated receptor activation α and behave as prototypical peroxisome proliferators . Other studies demonstrated that DEHP alters lipid metabolism in rat liver through the inhibition of the Janus Kinase/Signal Transduction and Activator of Transcription (JAK/STAT) pathway leading to an accumulation of triglycerides and thus to obesity . We have already gathered several evidences suggesting that DEHP is genotoxic in the liver by induction of DNA damage and activate the p53‐dependent apoptotic pathway in vivo and in vitro .…”