Hexokinase domain-containing protein-1 in metabolic diseases and beyond. (January 2022)

• Record Type: Journal Article
• Authors: Zapater, Joseph L.; Lednovich, Kristen R.; Khan, Md. Wasim; Pusec, Carolina M.; Layden, Brian T.
• Is Part Of: Trends in endocrinology and metabolism. Volume 33:Number 1(2022)
• Page Start: 72
• Page End: 84
• Publication Date: 2022-01
• Subjects: hexokinase -- HKDC1 -- glucose metabolism -- cancer; Endocrinology -- Periodicals; Metabolism -- Periodicals; Metabolism; 616.4
• DOI: 10.1016/j.tem.2021.10.006
• Languages: English
• ISSNs: 1043-2760

Abstract

Abstract : Glucose phosphorylation by hexokinases (HKs) traps glucose in cells and facilitates its usage in metabolic processes dependent on cellular needs. HK domain-containing protein-1 (HKDC1) is a recently discovered protein with wide expression containing HK activity, first noted through a genome-wide association study (GWAS) to be linked with gestational glucose homeostasis during pregnancy. Since then, HKDC1 has been observed to be expressed in many human tissues. Moreover, studies have shown that HKDC1 plays a role in glucose homeostasis by which it may affect the progression of many pathophysiological conditions such as gestational diabetes mellitus (GDM), nonalcoholic steatohepatitis (NASH), and cancer. Here, we review the key studies contributing to our current understanding of the roles of HKDC1 in human pathophysiological conditions and potential therapeutic interventions. Highlights: Hexokinase (HK) domain-containing protein-1 (HKDC1) is a widely expressed novel HK. Recent studies aimed at understanding the functionality of HKDC1 have identified roles for HKDC1 that extend beyond glucose sensing and phosphorylation. Genome-wide association studies have identified genetic variants of HKDC1 that are associated with 2-h blood glucose levels during an oral glucose tolerance test performed in pregnancy, as well as with hemoglobin A1c, suggesting a link between HKDC1 and diabetes. Mouse models indicate that HKDC1 is important for glucose utilization and homeostasis during times of metabolic stress. Beyond glucose metabolism, recent studies suggest roles for HKDC1 in the survival, progression, and metastases of several human cancers, conferring a poorer prognosis.