Exposure to 2,4-dichlorophenoxyacetic acid induced PPARβ-dependent disruption of glucose metabolism in HepG2 cells
- 41 Downloads
2,4-Dichlorophenoxyacetic acid is one of the most widely used herbicides. Its impact on health is increasingly attracting great attentions. This study aimed to investigate the effect of 2,4-dichlorophenoxyacetic acid on glucose metabolism in HepG2 cells and the underlying mechanism. After 24 h exposure to 2,4-dichlorophenoxyacetic acid, glycogen was measured by PAS staining and glucose by ELISA in HepG2 cells. The expression of genes involved in glucose metabolism was measured by real-time PCR, Western blotting, and immunofluorescence. HepG2 cells presented more extracellular glucose consumption and glycogen content after exposed to 2,4-dichlorophenoxyacetic acid. Expression of gluconeogenesis-related genes, FoxO1, and CREB is significantly elevated. Moreover, PPARβ was up-regulated dose-dependently. SiRNA knockdown of PPARβ completely rescued the increase of glycogen accumulation and glucose uptake, and the up-regulation of FOXO1 and CREB expression. Our findings propose novel mechanisms that 2,4-dichlorophenoxyacetic acid causes glucose metabolism dysfunction through PPARβ in HepG2 cells.
Keywords2,4-Dichlorophenoxyacetic acid PPARβ Herbicides Glucose metabolism Hepatocyte
This work was supported by grants from the National Natural Science Foundation of China (Grant No. 81570574).
Compliance with ethical standards
Conflict of interest
The authors declare that there is no conflict of interest.
- (USEPA) USEPA (2005) Reregistration eligibility decision for 2,4-D EPA 738-R-05-002Google Scholar
- (USEPA) USEPA (2017) Pesticides industry sales and usage: 2008–2012 market estimates. US Environmental Protection AgencyGoogle Scholar
- Erion DM, Ignatova ID, Yonemitsu S, Nagai Y, Chatterjee P, Weismann D, Hsiao JJ, Zhang D, Iwasaki T, Stark R, Flannery C, Kahn M, Carmean CM, Yu XX, Murray SF, Bhanot S, Monia BP, Cline GW, Samuel VT, Shulman GI (2009) Prevention of hepatic steatosis and hepatic insulin resistance by knockdown of cAMP response element-binding protein. Cell Metab 10:499–506. https://doi.org/10.1016/j.cmet.2009.10.007 CrossRefGoogle Scholar
- Harada Y, Tanaka N, Ichikawa M, Kamijo Y, Sugiyama E, Gonzalez FJ, Aoyama T (2016) PPARalpha-dependent cholesterol/testosterone disruption in Leydig cells mediates 2,4-dichlorophenoxyacetic acid-induced testicular toxicity in mice. Arch Toxicol 90:3061–3071. https://doi.org/10.1007/s00204-016-1669-z CrossRefGoogle Scholar
- Ngala RA, Stocker CJ, Roy AG, Hislop D, Wargent E, Bell R, Hassall DG, Harling JD, Billin AN, Willson TM, Arch JRS, Cawthorne MA (2011) A new, highly selective murine peroxisome proliferator-activated receptor delta agonist increases responsiveness to thermogenic stimuli and glucose uptake in skeletal muscle in obese mice. Diabetes Obes Metab 13:455–464. https://doi.org/10.1111/j.1463-1326.2011.01371.x CrossRefGoogle Scholar
- Ozaki K, Mahler JF, Haseman JK, Moomaw CR, Nicolette ML, Nyska A (2001) Unique renal tubule changes induced in rats and mice by the peroxisome proliferators 2,4-dichlorophenoxyacetic acid (2,4-D) and WY-14643. Toxicol Pathol 29:440–450. https://doi.org/10.1080/01926230152499791 CrossRefGoogle Scholar
- Tayeb W, Nakbi A, Cheraief I, Miled A, Hammami M (2013) Alteration of lipid status and lipid metabolism, induction of oxidative stress and lipid peroxidation by 2,4-dichlorophenoxyacetic herbicide in rat liver. Toxicol Mech Methods 23:449–458. https://doi.org/10.3109/15376516.2013.780275 CrossRefGoogle Scholar