Sodium nitrate protects against metabolic syndrome by sialin-mediated macrophage rebalance

Abstract 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 (NaNO 3 ) 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. NaNO 3 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 NaNO 3 protects against metabolic disorders through the actions of sialin in MoMFs. NaNO 3 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 NaNO 3 on metabolic syndrome and reveal a new macrophage rebalancing strategy involving NaNO 3 through a novel sialin pathway. Our research indicates that NaNO 3 may be a pharmaceutical agent for managing and alleviating metabolic turbulence in humans.