Hepatic gluconeogenesis is a critical process that generates glucose from non-carbohydrate precursors during fasting to support vital organs like the brain and red blood cells. Postprandially, this process is rapidly ...Hepatic gluconeogenesis is a critical process that generates glucose from non-carbohydrate precursors during fasting to support vital organs like the brain and red blood cells. Postprandially, this process is rapidly suppressed to allow for glucose storage as glycogen and lipids in the liver. Failure to suppress gluconeogenesis after meals leads to elevated postprandial glucose levels, a key feature of type 2 diabetes. This dynamic switch is regulated by insulin and glucagon, but insulin resistance impairs this regulation. In this study, we identified a novel mechanism involving postprandial circulating hyaluronan(HA) and lysosomal hyaluronidase-1(HYAL1) that suppresses hepatic gluconeogenesis by rewiring hepatic metabolism and mitochondrial function. Hyal1 knockout(Hyal1 KO) mice exhibited increased gluconeogenesis, while liver-specific Hyal1 overexpression(Liv-Hyal1) mice showed reduced gluconeogenic activity. Transcriptomic analysis revealed minimal changes in liver gene expression due to Hyal1 deletion, but metabolomic profiling demonstrated that Hyal1 overexpression mitigated high-fat diet(HFD)-induced elevations in gluconeogenic pathway metabolites. Mechanistically, HYAL1-mediated HA digestion activates a feedback loop in HA synthesis, repartitioning the cellular uridine diphospho-N-acetyl-D-glucosamine(UDP-Glc NAc) pool. This reduces O-linked N-acetylglucosamine modification(O-Glc NAcylation) of mitochondrial ATP synthase subunits, decreasing ATP production and suppressing gluconeogenesis. Importantly, this pathway remains intact in the livers of HFD-fed, insulin-resistant mice. In summary, our findings reveal a new postprandial mechanism for regulating hepatic gluconeogenesis, highlighting the potential of enhancing postprandial HA levels or hepatic HYAL1 activity as a therapeutic strategy for managing excessive gluconeogenesis in insulin-resistant conditions, such as type 2 diabetes.展开更多
基金supported by the USDA/ARS (cooperative agreement 3092-51000062)the NIH R01DK136532 and R01DK136619 to Y.Z.,the NIH R00AG068239,R01DK138035,and R01AG084646 to S.Z.,the NIH R00CA237618 and USDA/ARS (cooperative agreement 309251000-064) to X.G.+2 种基金the CPRIT Scholar in Cancer Research (RR210029) to D.G.supported by the CPRIT Core Facility Support Award RP210227 “Proteomic and Metabolomic Core Facility”,the NCI Cancer Center Support Grant P30CA125123,the NIH R01CA220297 and R01CA216426the intramural funds from the Dan L.Duncan Cancer Center (DLDCC) at the Baylor College of Medicine。
文摘Hepatic gluconeogenesis is a critical process that generates glucose from non-carbohydrate precursors during fasting to support vital organs like the brain and red blood cells. Postprandially, this process is rapidly suppressed to allow for glucose storage as glycogen and lipids in the liver. Failure to suppress gluconeogenesis after meals leads to elevated postprandial glucose levels, a key feature of type 2 diabetes. This dynamic switch is regulated by insulin and glucagon, but insulin resistance impairs this regulation. In this study, we identified a novel mechanism involving postprandial circulating hyaluronan(HA) and lysosomal hyaluronidase-1(HYAL1) that suppresses hepatic gluconeogenesis by rewiring hepatic metabolism and mitochondrial function. Hyal1 knockout(Hyal1 KO) mice exhibited increased gluconeogenesis, while liver-specific Hyal1 overexpression(Liv-Hyal1) mice showed reduced gluconeogenic activity. Transcriptomic analysis revealed minimal changes in liver gene expression due to Hyal1 deletion, but metabolomic profiling demonstrated that Hyal1 overexpression mitigated high-fat diet(HFD)-induced elevations in gluconeogenic pathway metabolites. Mechanistically, HYAL1-mediated HA digestion activates a feedback loop in HA synthesis, repartitioning the cellular uridine diphospho-N-acetyl-D-glucosamine(UDP-Glc NAc) pool. This reduces O-linked N-acetylglucosamine modification(O-Glc NAcylation) of mitochondrial ATP synthase subunits, decreasing ATP production and suppressing gluconeogenesis. Importantly, this pathway remains intact in the livers of HFD-fed, insulin-resistant mice. In summary, our findings reveal a new postprandial mechanism for regulating hepatic gluconeogenesis, highlighting the potential of enhancing postprandial HA levels or hepatic HYAL1 activity as a therapeutic strategy for managing excessive gluconeogenesis in insulin-resistant conditions, such as type 2 diabetes.
