Low-dose PCB126 compromises circadian rhythms associated with disordered glucose and lipid metabolism in mice

Abstract

It has been documented that 3, 3', 4, 4', 5-pentachlorobiphenyl (PCB126) elicits diverse detrimental effects on human health including metabolic syndrome and non-alcoholic fatty-liver disease (NAFLD), through a wide array of non-carcinogenic mechanisms, which require further detailed investigations. The circadian clock system consists of central clock machinery (located in the suprachiasmatic nucleus in the hypothalamus) and the peripheral clocks (located in nearly all peripheral tissues). Peripheral clocks in the liver play fundamental roles in maintaining liver homeostasis, including the regulation of energy metabolism and the expression of enzymes that fine-tune the absorption and metabolism of xenobiotics. However, the molecular basis of whether PCB126 disrupts liver homeostasis (e.g., glucose and lipid metabolism) by dysregulating the circadian clock system is still unknown. Thus, we performed a set of comprehensive analyses of glucose and lipid metabolism in the liver tissues from low-dose PCB126-treated mice. Our results demonstrated that PCB126 diminished glucose and cholesterol levels in serum and elevated glucose and cholesterol levels in the liver. Moreover, PCB126 compromised PGC1α and PDHE1α, which are the driving force for mitochondrial biogenesis and entry of pyruvate into the tricarboxylic acid (TCA) cycle, respectively, and resulted in the accumulation of glucose, glycogen and pyruvate in the liver after PCB126 exposure. Additionally, PCB126 blocked hepatic cholesterol metabolism and export pathways, leading to an elevated localization of hepatic cholesterol. Mechanistic investigations illustrated that PCB126 greatly altered the expression profile of core clock genes and their target rhythm genes involved in orchestrating glucose and cholesterol metabolism. Together, our results demonstrated that a close correlation between PCB126-disturbed glucose and lipid metabolism and disordered physiological oscillation of circadian genes.

Keywords: Cholesterol; Circadian rhythms; Glucose metabolism; Lipid metabolism; PCBs.