Hexokinase domain-containing protein-1 in metabolic diseases and beyond

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.

Keywords: HKDC1; cancer; glucose metabolism; hexokinase.

Figure 1:. Effects of modulation of HKDC1 protein expression on glucose homeostasis.

C57B1/6J mice were created such that they expressed 50% of wild-type HKDC1 protein in all tissues (left side, green boxes; see Box 1 for protocol) or selectively overexpressed or did not express hepatic HKDC1 (right side, orange boxes; see Box 2 for protocols). Mice displaying whole-body HKDC1 knockdown were assessed after an overnight fast using an OGTT consisting of a bolus of 2g/kg body weight glucose. During pregnancy and in aged mice, HKDC1 knockdown exhibit impaired blood glucose excursions during the OGTT and overall display reduced tissue glucose uptake and overall glucose tolerance. These findings were only found in pregnancy and with age, which are conditions of greater metabolic stress, and were not found in younger non-pregnant mice. Mice displaying liver-specific modulation of HKDC1 expression were assessed during pregnancy after an overnight fast using an intraperitoneal GTT consisting of a bolus of 2g/kg body weight glucose. Similar to whole-body HKDC1 knockdown, mice devoid of hepatic HKDC1 expression exhibited impaired tissue uptake of glucose and overall glucose tolerance after receiving the intraperitoneal glucose load, and also increased hepatic gluconeogenesis. On the contrary, mice overexpressing hepatic HKDC1 displayed the opposite findings, with improved tissue glucose uptake, glucose tolerance and insulin sensitivity, and indications of a shift in metabolism from glucose reliance to fat oxidation and ketone utilization during fasting due to the presence of increased ketone bodies.

Figure 2:. Synopsis of HKDC1 roles in human cancers.

The diagram represents a summary of key studies identifying and assessing alterations in the HKDC1 gene (a) and HKDC1 protein expression (b) found in corresponding human cancer tissues and cell lines. In the studies noted, findings were determined by comparing data obtained from cancerous human tissue samples or cancer cell lines to matching normal human tissue and cell lines. A key finding amongst the data is the finding that greater levels of HKDC1 in cancerous tissue correlates with increased proliferation, migration, and invasion, leading to a poorer overall prognosis and reduced survival. Abbreviations: AICAR, 5-aminoimidazole-4-carboxamide ribonucleotide (analog of adenosine monophosphate that stimulates AMPK activity); CRC, colorectal carcinoma; HCC, hepatocellular carcinoma; LUAD, lung adenocarcinoma; miRNA, microRNA; ROS, reactive oxygen species; siRNA, small interfering RNA; VDAC1, voltage dependent anion channel 1. Cell lines: SW480, human colon adenocarcinoma cell line, grade 3–4; SW620, metastatic human colon adenocarcinoma cell line obtained from lymph node; A549, non-small cell lung carcinoma cell line derived from adenocarcinomic lung tissue; H1299, metastatic non-small cell lung carcinoma cell line obtained from lymph node; MCF7, human breast cancer cell line.