Hyaluronidase-1 mediates postprandial suppression of hepatic gluconeogenesis

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

References

[1] Zhu Y , Crewe C , Scherer PE . Hyaluronan in adipose tissue:beyond dermal filler and therapeutic carrier. Sci Transl Med 2016; 8: 323ps4.

[2] Zhu Y , Kruglikov IL , Akgul Y et al. Hyaluronan in adipogenesis, adipose tissue physiology and systemic metabolism. Matrix Biol 2018; 78-79: 284- 91.

[3] Hascall V , and Esko JD . In: Varki A, Cummings RD, Esko JD, Stanley P, Hart GW, et al. eds. Essentials of Glycobiology. Cold Spring Harbor (NY); 2015: 197- 206.

[4] Weigel PH , Hascall VC , Tammi M . Hyaluronan synthases. J Biol Chem 1997; 272: 13997- 4000.

[5] Camenisch TD , Spicer AP , Brehm-Gibson T et al. Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme. J Clin Invest 2000; 106: 349- 60.

[6] Csoka AB , Frost GI , Stern R . The six hyaluronidase-like genes in the human and mouse genomes. Matrix Biol 2001; 20: 499- 508.

[7] Tengblad A , Laurent UB , Lilja K et al. Concentration and relative molecular mass of hyaluronate in lymph and blood. Biochem J 1986; 236: 521- 5.

[8] Fraser JR , Laurent TC . Turnover and metabolism of hyaluronan. Ciba Found Symp 1989; 143: 41- 53.

[9] Eriksson S , Fraser JR , Laurent TC et al. Endothelial cells are a site of uptake and degradation of hyaluronic acid in the liver. Exp Cell Res 1983; 144: 223- 8.

[10] Alston-Smith J , Pertoft H , Laurent TC . Endocytosis of hyaluronan in rat Kupffer cells. Biochem J 1992; 286: 519- 26.

[11] Puissant E , Gilis F , Dogne S et al. Subcellular trafficking and activity of Hyal-1 and its processed forms in murine macrophages. Traffic. 2014; 15: 500- 15.

[12] Bourguignon V , Flamion B . Respective roles of hyaluronidases 1 and 2 in endogenous hyaluronan turnover. FASEB J 2016; 30: 2108- 14.

[13] Caon I , Parnigoni A , Viola M et al. Cell energy metabolism and hyaluronan synthesis. J Histochem Cytochem 2021; 69: 35- 47.

[14] Love DC , Hanover JA . The hexosamine signaling pathway:deciphering the "O-GlcNAc code". Sci STKE 2005; 2005: re13.

[15] MacNicholl AD , Wusteman FS , Winterburn PJ et al. Degradation of[3H]chondroitin 4-sulphate and re-utilization of the[3H] hexosamine component by the isolated perfused rat liver. Biochem J 1980; 186: 279- 86.

[16] Zhu Y , Li N , Huang M et al. Adipose tissue hyaluronan production improves systemic glucose homeostasis and primes adipocytes for CL 316,243-stimulated lipolysis. Nat Commun 2021; 12: 4829.

[17] Rui L . Energy metabolism in the liver. Compr Physiol. 2014; 4: 177- 97.

[18] Van Dop C , Medynski DC , Apone LM . Nucleotide sequence for a cDNA encoding the alpha subunit of retinal transducin (GNAT1) isolated from the human eye. Nucleic Acids Res 1989; 17: 4887.

[19] Uhlen M , Fagerberg L , Hallstrom BM et al. Proteomics. Tissuebased map of the human proteome. Science 2015; 347: 1260419.

[20] Cao W , Cao J , Huang J et al. Discovery and confirmation of O-GlcNAcylated proteins in rat liver mitochondria by combination of mass spectrometry and immunological methods. PLoS One 2013; 8: e76399.

[21] Acin-Perez R , Beninca C , Fernandez Del Rio L et al. Inhibition of ATP synthase reverse activity restores energy homeostasis in mitochondrial pathologies. EMBO J 2023; 42: e111699.

[22] Kresse H , Glossl J . Glycosaminoglycan degradation. Adv Enzymol Relat Areas Mol Biol 1987; 60: 217- 311.

[23] Cha MY , Cho HJ , Kim C et al. Mitochondrial ATP synthase activity is impaired by suppressed O-GlcNAcylation in Alzheimer's disease. Hum Mol Genet 2015; 24: 6492- 504.

[24] Kreppel LK , Blomberg MA , Hart GW . Dynamic glycosylation of nuclear and cytosolic proteins. Cloning and characterization of a unique O-GlcNAc transferase with multiple tetratricopeptide repeats. J Biol Chem 1997; 272: 9308- 15.

[25] Love DC , Kochan J , Cathey RL et al. Mitochondrial and nucleocytoplasmic targeting of O-linked GlcNAc transferase. J Cell Sci 2003; 116: 647- 54.

[26] Aharoni-Simon M , Hann-Obercyger M , Pen S et al. Fatty liver is associated with impaired activity of PPARγ-coactivator 1α (PGC1α) and mitochondrial biogenesis in mice. Lab Invest 2011; 91: 1018- 28.

[27] Cortez-Pinto H , Chatham J , Chacko VP et al. Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis:a pilot study. JAMA 1999; 282: 1659- 64.

[28] Chavin KD , Yang S , Lin HZ et al. Obesity induces expression of uncoupling protein-2 in hepatocytes and promotes liver ATP depletion. J Biol Chem 1999; 274: 5692- 700.

[29] Barroso E , Jurado-Aguilar J , Wahli W et al. Increased hepatic gluconeogenesis and type 2 diabetes mellitus. Trends Endocrinol Metab 2024; 35: 1062- 77.

[30] Caldara R , Testori GP , Ferrari C et al. Effect of loperamide, a peripheral opiate agonist, on circulating glucose, free fatty acids, insulin, C-peptide and pituitary hormones in healthy man. Eur J Clin Pharmacol 1981; 21: 185- 8.

[31] Martin DC , Atmuri V , Hemming RJ et al. A mouse model of human mucopolysaccharidosis IX exhibits osteoarthritis. Hum Mol Genet 2008; 17: 1904- 15.

[32] Dogne S , Rath G , Jouret F et al. Hyaluronidase 1 deficiency preserves endothelial function and glycocalyx integrity in early streptozotocin-induced diabetes. Diabetes 2016; 65: 2742- 53.

[33] Sun K , Wernstedt Asterholm I , Kusminski CM et al. Dichotomous effects of VEGF-A on adipose tissue dysfunction. Proc Natl Acad Sci U S A 2012; 109: 5874- 9.

[34] Postic C , Shiota M , Niswender KD et al. Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic β cell-specific gene knock-outs using Cre recombinase. J Biol Chem 1999; 274: 305- 15.

[35] Belteki G , Haigh J , Kabacs N et al. Conditional and inducible transgene expression in mice through the combinatorial use of Cre-mediated recombination and tetracycline induction. Nucleic Acids Res 2005; 33: e51.

[36] Zhu Y , Pereira RO , O'Neill BT et al. Cardiac PI3K-Akt impairs insulin-stimulated glucose uptake independent of mTORC1 and GLUT4 translocation. Mol Endocrinol 2013; 27: 172- 84.

[37] Huang M , Mathew N , Zhu Y . Assessing whole-body lipidhandling capacity in mice. J Vis Exp 2020; (165): 10.3791/61927.

[38] Wangler MF , Chao YH , Bayat V et al. Peroxisomal biogenesis is genetically and biochemically linked to carbohydrate metabolism in Drosophila and mouse. PLoS Genet 2017; 13: e1006825.

[39] Gusdon AM , Fu C , Putluri V et al. Early systemic glycolytic shift after aneurysmal subarachnoid hemorrhage is associated with functional outcomes. Neurocrit Care 2022; 37: 724- 34.

[40] Wang X , Spandidos A , Wang H et al. PrimerBank:a PCR primer database for quantitative gene expression analysis, 2012 update. Nucleic Acids Res 2012; 40: D1144- 9.

[41] Zhu Y , Pires KM , Whitehead KJ et al. Mechanistic target of rapamycin (Mtor) is essential for murine embryonic heart development and growth. PLoS One 2013; 8: e54221.

[42] Ewels P , Magnusson M , Lundin S et al. MultiQC:summarize analysis results for multiple tools and samples in a single report. Bioinformatics 2016; 32: 3047- 8.

[43] Love MI , Huber W , Anders S . Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 2014; 15: 550.

[44] Liao PC , Bergamini C , Fato R et al. Isolation of mitochondria from cells and tissues. Methods Cell Biol 2020; 155: 3- 31.

[45] Chen X , Li H , Liu Y et al. Dimethyl sulfoxide inhibits bile acid synthesis in healthy mice but does not protect mice from bile-acid-induced liver damage. Biology (Basel) 2023; 12: 1105.

[46] Liu HY , Collins QF , Xiong Y et al. Prolonged treatment of primary hepatocytes with oleate induces insulin resistance through p38 mitogen-activated protein kinase. J Biol Chem 2007; 282: 14205- 12.

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