Introduction: Many gene products have diverse and surprising functions. One such candidate is ectonucleotide pyrophosphatase/phosphodiesterase 6 (ENPP6) which was identified in 2005 and is highly expressed by endothelial cells and developing oligodendrocytes. ENPP6, a choline-specific phosphodiesterase, which hydrolyses glycerophosphocholine, a degradation product of the phospholipid, phosphatidylcholine and is a key enzyme in choline metabolism. ENPP6 also possesses lysophospholipase C activity and exhibits high specificity towards lysophosphatidylcholine and thereby capable of generating phosphocholine.
Work leading up to this project: CF and AJS have reported that a bone specific phosphatase – PHOSPHO1 - exhibits specificity towards phosphocholine, releasing inorganic phosphate to promote mineral crystal formation. This has recently led us to hypothesise that phospholipase A2 (PLA2), which can liberate lysophosphatidylcholine from phosphatidylcholine, may sequentially act together with ENPP6 to produce phosphocholine - a substrate for PHOSPHO1 (Stewart et al. 2018). This concept is supported by data showing the expression of ENPP6, PLA2 and PHOSPHO1 in bone and that phosphatidylcholine is broken down at the initial sites of mineralisation. Independently of this work NM has identified single nucleotide polymorphisms in and around ENPP6 that associate with reduced visceral adiposity in humans. Moreover, Enpp6 gene knockout mice resist visceral obesity and diabetes with a high fat diet challenge, suggesting a major role for ENPP6 in metabolic homeostasis (unpublished work).
These data support the growing notion that bone is a key endocrine regulator of metabolism and energy balance, a concept our group have pioneered (Huesa et al., 2014). It is however unclear if the role of ENPP6 in bone mineralisation and energy production are linked or independent of each other.
Approach: The aims of this interdisciplinary studentship will be to investigate ENPP6 mode of function in regulating bone and nutrient metabolism. The project will benefit from supervision by a skeletal biologist (Farquharson), biochemist (Stewart) and specialist in metabolism/metabolic disease modelling (Morton). This project will expose the student to wide-ranging fields of research including: bone development, lipid/nutrient metabolism, endocrinology as well as genetics and protein biochemistry/biophysics. The Universities of Edinburgh and St Andrews both provide an outstanding environment to carry out research and it is expected the student will spend some time in each of the supervisor’s laboratories.
Training: The student will engage with world-leading scientists and receive excellent support and training opportunities through the University of Edinburgh’s IAD training programme, University of St Andrews award-winning GRADskills programme and EASTBIO’s thematic training. The student will be trained in mouse colony (transgenic and knock-out) management and cell and molecular techniques including, cell imaging (by various forms of microscopy), cell-based gene/protein expression assays, recombinant protein production and purification, biophysical techniques (e.g. SPR, calorimetry) structural biology and cellular and whole animal energetics (Morton et al., 2016). Throughout the project the student will gain experience in data collection, data interpretation and writing papers for publication. The student will be expected to engage with other scientists in the respective institutes and to attend and present their findings at local laboratory meetings as well as UK and international conferences.
1. Stewart AJ, Leong DTK, Farquharson C. (2018) PLA2 and ENPP6 may act in concert to generate phosphocholine from the matrix vesicle membrane during skeletal mineralization. FASEB J. 32: 20-25.
2. Huesa C, Zhu D, Glover JD, Ferron M, Karsenty G, Milne EM, Millan JL, Ahmed SF, Farquharson C, Morton NM, MacRae VE. (2014) Deficiency of the bone mineralization inhibitor NPP1 protects against obesity and diabetes. Dis Model Mech. 12:1341-1350
3. Morton NM, Beltram J, Carter RN, Michailidou Z, Gorjanc G, McFadden C, Barrios-Llerena ME, Rodriguez-Cuenca S, Gibbins MT, Aird RE, Moreno-Navarrete JM, Munger SC, Svenson KL, Gastaldello A, Ramage L, Naredo G, Zeyda M, Wang ZV, Howie AF, Saari A, Sipilä P, Stulnig TM, Gudnason V, Kenyon CJ, Seckl JR, Walker BR, Webster SP, Dunbar DR, Churchill GA, Vidal-Puig A, Fernandez-Real JM, Emilsson V, Horvat S. Genetic identification of thiosulfate sulfurtransferase as an adipocyte-expressed antidiabetic target in mice selected for leanness. Nat Med. 2016 22:771-9.