BackgroundAlthough the prolonged use of rapamycin may cause unwanted side effects such as hyperlipidemia, the underlying mechanism remains unknown. Prox1 is a transcription factor responsible for the development of several tissues including lymphatics and liver. There is growing evidences that Prox1 participates in metabolism in addition to embryogenesis. However, whether Prox1 is directly related to lipid metabolism is currently unknown.MethodsHepG2 human hepatoma cells were treated with rapamycin and total lipids were analyzed by thin layer chromatography. The effect of rapamycin on the expression of Prox1 was determined by western blotting. To investigate the role of Prox1 in triglycerides regulation, siRNA and overexpression system were employed. Rapamycin was injected into mice for 2 weeks and total lipids and proteins in liver were measured by thin layer chromatography and western blot analysis, respectively.ResultsRapamycin up-regulated the amount of triglyceride and down-regulated the expression of Prox1 in HepG2 cells by reducing protein half-life but did not affect its transcript. The loss-of-function of Prox1 was coincident with the increase of triglycerides in HepG2 cells treated with rapamycin. The up-regulation of triglycerides by rapamycin in HepG2 cells reverted to normal levels by the compensation of Prox1 using the overexpression system. Rapamycin also down-regulated Prox1 expression but increased triglycerides in mouse liver.ConclusionThis study suggests that rapamycin can increase the amount of triglycerides by down-regulating Prox1 expression in hepatocytes, which means that the mammalian target of rapamycin (mTOR) signaling is important for the regulation of triglycerides by maintaining Prox1 expression.

Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α) is a potent transcription factor for mitochondrial function, lipid metabolism, and detoxification in a variety of tissues. PGC1α also promotes brain cell proliferation and memory. However, how PGC1α is involved in aging is not well known. In brain endothelial cells, we found that PGC1α knockdown accelerated DNA damage-induced senescence, evidenced by an increase in senescence-associated γ-galactosidase-positive cells and a decrease in cell proliferation and ATP production. PGC1α knockdown delayed DNA damage repair mechanisms compared with the wild-type condition as shown by γ-H2AX foci staining assay. Overexpression of PGC1α reduced senescence-associated γ-galactosidase-positive cells and increased the proliferation of senescent cells. Although PGC1α protein levels were not decreased, PGC1 acetylation was increased by ionizing radiation treatment and aging. Histone deacetylase 1 (HDAC1) expression was decreased by ionizing radiation treatment and aging, and downregulation of HDAC1 induced acetylation of PGC1α. HDAC1 knockdown affected sirtuin 1 expression and decreased its deacetylation of PGC1α. In the mouse brain cortex, acetylation of PGC1α was increased by ionizing radiation treatment. These results suggest that acetylation of PGC1α is induced by DNA damage agents such as ionizing radiation, which deregulates mitochondrial mechanisms and metabolism, resulting in acceleration of radiation-induced senescence. Therefore, acetylation of PGC1α may be a cause of brain disorders and has the potential to serve as a therapeutic target for radiation-induced senescence after radiation cancer therapy.