SUCNR1 coordinates metabolic flux, mitochondrial function, and nutrient-dependent adaptation in hepatocytes

Succinate, a mitochondrial metabolite, also functions as an extracellular signal through its receptor succinate receptor 1 (SUCNR1), coordinating responses to nutrient availability. The physiological role of SUCNR1 within hepatocytes, however, is unclear. We show that hepatic succinate levels and Sucnr1 expression are dynamically regulated by nutritional status. Mice lacking Sucnr1 in hepatocytes [Hep-Sucnr1 knockout (KO)] exhibit a fasting-like phenotype characterized by enhanced gluconeogenesis, elevated amino acids, and impaired metabolic flexibility. Mechanistically, loss of Sucnr1 compromises glucose-derived oxidative flux through the tricarboxylic acid cycle, increases reliance on glutamine-dependent anaplerosis, and induces mitochondrial stress adaptations. Upon refeeding, Hep-Sucnr1 KO mice show blunted mammalian target of rapamycin activation, incomplete glycogen restoration, and an altered hepatic proteomic response. Sucnr1 expression increases during liver maturation, is enriched in pericentral hepatocytes, and its loss is associated with functional reprogramming of pericentral metabolic functions without disruption of zonation. Together, our findings establish SUCNR1 as a critical regulator of hepatic metabolic adaptation, linking succinate signaling to mitochondrial flexibility and nutrient-dependent metabolic responses.