Abstract
Simple SummaryMultidrug resistance proteins (MRPs) are important for ion transport, toxin/xenobiotic secretion, and signal transduction. Although studies have been undertaken to understand their physiological function, it is not fully known how MRPs may regulate metabolism. We knocked down the expression of Drosophila multidrug-resistance like protein 1 (MRP) in several tissues central to metabolic regulation. Reducing MRP in Malpighian tubules, the functional equivalent to the human kidney, was sufficient to disrupt metabolic homeostasis, owing to abnormal lipid accumulation, as well as changes in feeding behavior. It also increased oxidative stress resistance in adult flies, possibly due to reduced levels of reactive oxygen species.Multidrug resistance proteins (MRPs), members of the ATP-binding cassette transporter (ABC transporter) family, are pivotal for transporting endo- and xenobiotics, which confer resistance to anticancer agents and contribute to the clearance of oxidative products. However, their function in many biological processes is still unclear. We investigated the role of an evolutionarily conserved MRP in metabolic homeostasis by knocking down the expression of Drosophila multidrug-resistance like protein 1 (MRP) in several tissues involved in regulating metabolism, including the gut, fat body, and Malpighian tubules. Interestingly, only suppression of MRP in the Malpighian tubules, the functional equivalent to the human kidney, was sufficient to cause abnormal lipid accumulation and disrupt feeding behavior. Furthermore, reduced Malpighian tubule MRP expression resulted in increased Hr96 (homolog of human pregnane X receptor) expression. Hr96 is known to play a role in detoxification and lipid metabolism processes. Reduced expression of MRP in the Malpighian tubules also conveyed resistance to oxidative stress, as well as reduced normal levels of reactive oxygen species in adult flies. This study reveals that an evolutionarily conserved MRP is required in Drosophila Malpighian tubules for proper metabolic homeostasis.
Highlights
Drosophila multidrug resistance proteins (MRPs) is highly expressed in the gut and Malpighian tubules and at lower levels in the fat body [22,25]
UAS-MRP RNAi flies with four tissue-specific GAL4 drivers, namely a mid-gut driver
We found that when MRP was knocked down in the Malpighian tubules, which are functionally similar to the mammalian kidney, flies were significantly more resistant to starvation
Summary
The ATP-binding cassette transporters (ABC transporters) are one of the largest transporter families. These transporters take part in cellular substrate influx and efflux. Among ABC transporters, the multidrug resistance proteins (MRPs), known as ABCCs and GS-X pumps, belong to the C subfamily and have been shown to contribute to ion transport, toxin/xenobiotic secretion, and signal transduction [1,2]. Due to the ubiquity of MRP expression, numerous studies have been performed on their physiological functions [3,4]. The evolutionarily conserved MRP family member multidrug resistance protein 1 (MRP1) Due to the ubiquity of MRP expression, numerous studies have been performed on their physiological functions [3,4]. 4.0/).
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