Metabolic syndrome,characterized by metabolic dysfunction-associated steatotic liver disease(MASLD)and type 2 diabetes mellitus(T2DM),poses a significant threat to patients'health worldwide;however,efficient treat...Metabolic syndrome,characterized by metabolic dysfunction-associated steatotic liver disease(MASLD)and type 2 diabetes mellitus(T2DM),poses a significant threat to patients'health worldwide;however,efficient treatment is currently unavailable.Here,we show that oral administration of sodium nitrate(NaNO3)greatly attenuates the development and advancement of MASLD-like and T2DM-like phenotypes in mice induced by choline-deficient high-fat,western,or methionine/choline-deficient diet.NaNO3 attenuates metabolic turbulence by rebalancing CD206+/CD11C+polarization(anti-inflammatory/pro-inflammatory)and the function of bone marrow-derived macrophages(MoMFs).Using metabolic disorder animal models and bone marrow-reconstituted mice with mutated gene function in Slc17a5,which encodes sialin,we demonstrate that NaNO3 protects against metabolic disorders through the actions of sialin in MoMFs.NaNO3 can directly regulate MoMFs polarization and function in vitro and in mice,in which nitric oxide production from oral and enteral symbiotic bacteria is essentially abolished.At the molecular level,sialin,via the inhibition of the key transcription factor Rel,inhibits cathepsin L(CtsL)expression and thereby activates the Nrf2 pathway to modulate macrophage homeostasis and ameliorate metabolic abnormalities.Interestingly,the sialin-CtsL-Nrf2 pathway is downregulated in human macrophages from metabolic dysfunction-associated steatohepatitis(MASH)patients.Overall,we demonstrate the prophylactic and therapeutic effects of NaNO3 on metabolic syndrome and reveal a new macrophage rebalancing strategy involving NaNO3 through a novel sialin pathway.Our research indicates that NaNO3 may be a pharmaceutical agent for managing and alleviating metabolic turbulence in humans.展开更多
基金funding by the National Natural Science Foundation of China(82201054,82030031,L2224038)the Beijing Municipal Government grant(Beijing Laboratory of Oral Health,PXM2021-014226-000041)+4 种基金the Beijing Municipal Science and Technology Commission(Z181100001718208)the Beijing Stomatological Hospital,Capital Medical University Young Scientist Program(YSP202102)the Innovation Research Team Project of Beijing Stomatological Hospital,Capital Medical University(CXTD202201)the Beijing Municipal Government(Beijing Scholar Program,PXM2020_014226_000005 and PXM2021_014226_000020)State Key Laboratory of Oral Diseases,Sichuan University(SKLOD2023OF13)。
文摘Metabolic syndrome,characterized by metabolic dysfunction-associated steatotic liver disease(MASLD)and type 2 diabetes mellitus(T2DM),poses a significant threat to patients'health worldwide;however,efficient treatment is currently unavailable.Here,we show that oral administration of sodium nitrate(NaNO3)greatly attenuates the development and advancement of MASLD-like and T2DM-like phenotypes in mice induced by choline-deficient high-fat,western,or methionine/choline-deficient diet.NaNO3 attenuates metabolic turbulence by rebalancing CD206+/CD11C+polarization(anti-inflammatory/pro-inflammatory)and the function of bone marrow-derived macrophages(MoMFs).Using metabolic disorder animal models and bone marrow-reconstituted mice with mutated gene function in Slc17a5,which encodes sialin,we demonstrate that NaNO3 protects against metabolic disorders through the actions of sialin in MoMFs.NaNO3 can directly regulate MoMFs polarization and function in vitro and in mice,in which nitric oxide production from oral and enteral symbiotic bacteria is essentially abolished.At the molecular level,sialin,via the inhibition of the key transcription factor Rel,inhibits cathepsin L(CtsL)expression and thereby activates the Nrf2 pathway to modulate macrophage homeostasis and ameliorate metabolic abnormalities.Interestingly,the sialin-CtsL-Nrf2 pathway is downregulated in human macrophages from metabolic dysfunction-associated steatohepatitis(MASH)patients.Overall,we demonstrate the prophylactic and therapeutic effects of NaNO3 on metabolic syndrome and reveal a new macrophage rebalancing strategy involving NaNO3 through a novel sialin pathway.Our research indicates that NaNO3 may be a pharmaceutical agent for managing and alleviating metabolic turbulence in humans.
