Language

English

Publication Date

10-1-2025

Journal

Life Metabolism

DOI

10.1093/lifemeta/loaf016v

PMID

42058136

PMCID

PMC13122362

PubMedCentral® Posted Date

5-13-2025

PubMedCentral® Full Text Version

Post-print

Abstract

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-GlcNAc) pool. This reduces O-linked N-acetylglucosamine modification (O-GlcNAcylation) 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.

Keywords

HYAL1, hyaluronan, hepatic gluconeogenesis, metabolites, mitochondrial function

Published Open-Access

yes

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