Inhibiting glutamine metabolism has been proposed as a potential treatment strategy for improving non-alcoholic steatohepatitis(NASH).However,effective methods for assessing dynamic metabolic responses during interven...Inhibiting glutamine metabolism has been proposed as a potential treatment strategy for improving non-alcoholic steatohepatitis(NASH).However,effective methods for assessing dynamic metabolic responses during interventions targeting glutaminolysis have not yet emerged.Here,we developed a positron emission tomography(PET)imaging platform using l-[5-^(11)C]glutamine([^(11)C]Gln)and evaluated its efficacy in NASH mice undergoing metabolic therapy with bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide(BPTES),a glutaminase 1(GLS1)inhibitor that intervenes in the first and rate-limiting step of glutaminolysis.PET imaging with[^(11)C]Gln effectively delineated the pharmacokinetics of l-glutamine,capturing its temporal-spatial pattern of action within the body.Furthermore,[^(11)C]Gln PET imaging revealed a significant increase in hepatic uptake in methionine and choline deficient(MCD)-fed NASH mice,whereas systemic therapeutic interventions with BPTES reduced the hepatic avidity of[^(11)C]Gln in MCD-fed mice.This reduction in[^(11)C]Gln uptake correlated with a decrease in GLS1 burden and improvements in liver damage,indicating the efficacy of BPTES in mitigating NASH-related metabolic abnormalities.These results suggest that[^(11)C]Gln PET imaging can serve as a noninvasive diagnostic platform for whole-body,real-time tracking of responses of glutaminolysis to GLS1 manipulation in NASH,and it may be a valuable tool for the clinical management of patients with NASH undergoing glutaminolysis-based metabolic therapy.展开更多
基金supported in part by the Moonshot Research and Development Program(Grant No.21zf0127003h001,Japan)JSPS A3 Foresight Program(Grant No.JPJSA3F20230001,Japan)JSPS KAKENHI(Grants No.23H02867,23H05487,and 21K07659,Japan).
文摘Inhibiting glutamine metabolism has been proposed as a potential treatment strategy for improving non-alcoholic steatohepatitis(NASH).However,effective methods for assessing dynamic metabolic responses during interventions targeting glutaminolysis have not yet emerged.Here,we developed a positron emission tomography(PET)imaging platform using l-[5-^(11)C]glutamine([^(11)C]Gln)and evaluated its efficacy in NASH mice undergoing metabolic therapy with bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide(BPTES),a glutaminase 1(GLS1)inhibitor that intervenes in the first and rate-limiting step of glutaminolysis.PET imaging with[^(11)C]Gln effectively delineated the pharmacokinetics of l-glutamine,capturing its temporal-spatial pattern of action within the body.Furthermore,[^(11)C]Gln PET imaging revealed a significant increase in hepatic uptake in methionine and choline deficient(MCD)-fed NASH mice,whereas systemic therapeutic interventions with BPTES reduced the hepatic avidity of[^(11)C]Gln in MCD-fed mice.This reduction in[^(11)C]Gln uptake correlated with a decrease in GLS1 burden and improvements in liver damage,indicating the efficacy of BPTES in mitigating NASH-related metabolic abnormalities.These results suggest that[^(11)C]Gln PET imaging can serve as a noninvasive diagnostic platform for whole-body,real-time tracking of responses of glutaminolysis to GLS1 manipulation in NASH,and it may be a valuable tool for the clinical management of patients with NASH undergoing glutaminolysis-based metabolic therapy.
