Dietary Methionine Restriction Upregulates Endogenous H₂ S via miR-328-3p: A Potential Mechanism to Improve Liver Protein Metabolism Efficiency in a Mouse Model of High-fat-diet-induced Obesity

SCOPE: Dietary methionine restriction (MR) promotes multifaceted health benefits. Moreover, lower rate of protein synthesis by dietary MR is associated with life span extension. The goal of this work is to explore how dietary MR would affect protein metabolism in a mouse model of high-fat-diet-induced obesity (DIO). METHODS AND RESULTS: DIO mice (male C57BL/6) are subjected to dietary MR for 22 weeks. High-throughput sequencing technology, qRT-PCR analysis, and the dual luciferase reporter assay are performed to verify that MiR-328-3p directly targets cystathionine γ-lyase (CSE) to modulate endogenous H₂ S production. Moreover, indicators of endogenous H₂ S, fractional synthesis rate (FSR), fractional growth rate (FGR), fractional degradation rate (FDR), and protein retention efficiency (PRE) are analyzed. MR results in an increase in endogenous H₂ S to relieve oxidative stress and ER stress to improve protein homeostasis and metabolic efficiency in DIO mice. CONCLUSION: Results show that dietary MR increases endogenous H₂ S production via miR-328-3p. Furthermore, these results suggest the potential involvement of endogenous H₂ S on the efficiency of protein metabolism in dietary MR.