Project description:N-lactoyl-phenylalanine (Lac-Phe) is a lactate-derived metabolite that suppresses food intake and body weight. Little is known about the mechanisms that mediate Lac-Phe transport across cell membranes. Here we identify SLC17A1 and SLC17A3, two kidney-restricted plasma membrane-localized solute carriers, as physiologic urine Lac-Phe transporters. In cell culture, SLC17A1/3 exhibit high Lac-Phe efflux activity. In humans, levels of Lac-Phe in urine exhibit a strong genetic association with the SLC17A1-4 locus. Urine Lac-Phe levels are also increased following a Wingate sprint test. In mice, genetic ablation of either SLC17A1 or SLC17A3 reduces urine Lac-Phe levels. Despite these differences, both knockout strains have normal blood Lac-Phe and body weights, demonstrating SLC17-dependent de-coupling of urine and plasma Lac-Phe pools. Together, these data establish SLC17A1/3 family members as the physiologic urine transporters for Lac-Phe and uncover a biochemical pathway for the renal excretion of this signaling metabolite. Our data do not exclude the involvement of other transporters in mediating Lac-Phe transport.
Project description:Many solid tumors grow slowly, with an average volume doubling time of several months to multiple years. Yet, most studies to date have focused mainly on the short-term fate of cancerous cells upon exposure to acidic pHe (extracellular pH), a common hallmark of tumor microenvironment. Little is known about how solid tumors, such as intractable PDAC originated from pancreatic ductal cells that secrete alkaline fluids, evolve to tolerate and adapt to the sustained and prolonged exposure of acidic pHe stress. We established a series of PDAC tumor cells exposed to prolonged periods of extracellular acidification. These biological materials were further subjected to microarray analysis to detail the genome-wide gene expression profiles and to identify the differential expressed genes related to the long-term adaptation of PDAC tumor cells to the extracellular chronic acidosis stress.
