L-[5-11C]glutamine PET monitors dynamic responses of glutaminolysis to interventions targeting glutaminase 1 in non-alcoholic steatohepatitis

Introduction: Interventions targeting glutaminolysis has been proposed as a potential treatment strategy for non-alcoholic steatohepatitis (NASH).^1,2 However, effective methods for assessing dynamic metabolic responses during interventions targeting glutaminolysis have not yet emerged. In this study, we developed a positron emission tomography (PET) imaging platform using L-[5-¹¹C]glutamine ([¹¹C]Gln) and evaluated its efficacy in NASH mice, as well as during metabolic therapy with bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) (Fig. 1).

Methods: Utilising [¹¹C]Gln PET, we tracked the dynamic response of glutaminolysis under normal physiological conditions, in murine models of NASH induced by methionine and choline deficient (MCD) diet,³ and following therapeutic interventions with BPTES, a glutaminase 1 (GLS1) inhibitor that intervenes in the first and rate-limiting step of glutaminolysis.^1,2 Histopathological and genetic analyses were performed to evaluate and quantify hepatic GLS1 levels and liver pathologies.

Results: PET imaging with [¹¹C]Gln effectively delineated the pharmacokinetics of L-glutamine, capturing its temporal-spatial pattern of action within the body. Furthermore, [¹¹C]Gln PET imaging revealed a significant increase in hepatic uptake in NASH mice, whereas systemic therapeutic interventions with BPTES reduced the hepatic avidity of [¹¹C]Gln in MCD diet-fed mice(Fig. 1A-B). This reduction in [¹¹C]Gln uptake correlated with a decrease in the GLS1 burden and improvements in liver damage, suggesting the efficacy of BPTES in mitigating NASH-related metabolic abnormalities(Fig. 1C).

Conclusions: These results suggest that [¹¹C]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.

References

• Johmura Y, Yamanaka T, Omori S, et al. Science 2021;371:265-270.

• Simon J, Nuñez-García M, Fernández-Tussy P, et al. T Cell Metab 2020;31:605-622.e610.

• Xie L, Yui J, Hatori A, et al. J Hepatol 2012;57:1076-1082.

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