Professor William Griffiths

BSc PhD FRSC

Research

https://orcid.org/0000-0002-4129-6616

Our research is focused on cholesterol biosynthesis and metabolism and how disorders in these pathways can lead to disease. Our primary technology is mass spectrometry which we use to measure quantities of cholesterol precursors and metabolites, i.e. sterolomics, in biological samples. We have recently extended this technology to mass spectrometry imaging.

Unusual Cholesterol Metabolites in Disease

Tuberculosis (TB), an infection caused by Mycobacterium tuberculosis (Mtb), remains the leading  infectious disease killer worldwide, claiming more than 1 million lives each year. In a recent study with Washington University in St. Louis School of Medicine we found that Mtb converts bioactive cholesterol metabolites (oxysterols) with inflammatory functions important in host defence into novel metabolites which are inactive. This impairs macrophage cholesterol homeostasis generating treatment-responsive metabolic signatures in human TB.

·       Mycobacterium tuberculosis inactivates host oxysterols to impair macrophage cholesterol homeostasis

Lipidomics and Metabolomics for Rare Disease Diagnosis

Cardiff University now hosts the Rare Disease Research UK node “Lipidomics and metabolomics for Rare Disease Diagnosis”. The goal of our node is to use Lipidomics and Metabolomics technologies to help people with a rare disease get a diagnosis faster, and then assist in monitoring response to therapy.

·       Rare Cholesterol Related Disorders – A Sterolomic Library for Diagnosis and Monitoring of Diseases

·       Deletion of CH25H and LIPA Genes in Human Abolishes Biosynthesis of 25-Hydroxycholesterol but not of 7α,25-Dihydroxysterols and Enhances Non-enzymatic Cholesterol Oxidation: Metabolic Changes are Partially Reversed by Hematopoietic Stem Cell Transplant

This work is funded by the Medical Research Council (MR/Y008057/1).

Cholesterol and Huntington’s Disease

Disturbed cholesterol metabolism is implicated in the progression of Huntington’s disease (HD). In a recent study of plasma and cerebrospinal fluid from people with manifest HD, premanifest HD and controls we found that the brain derived cholesterol metabolite, 24S-hydroxycholesterol, is present at lower concentrations in plasma from people in the manifest HD group than in the other two groups. This work indicates plasma concentrations of 24S-hydroxycholesterol as a potential biomarker for HD progression and response to treatment. Two cholesterol precursors, 7-dehydrocholesterol and 8-dehydrocholesterol, were found to be elevated in both CSF and plasma from people in the manifest HD group. This implicates a deficiency in the enzyme 7-dehydrocholesterol reductase in HD progression.

·       24S-Hydroxycholesterol: A potential brain-derived biomarker of Huntington’s Disease

·       Huntington's Disease Association - A postcard from Dubrovnik

This work was funded by the CHDI foundation.

Cholesterol and Other Neurodegenerative Disease

Cholesterol makes up about 2% of the wet weight of the brain and 25% of body cholesterol is found in brain, so it is not surprising that cholesterol is linked with neurodegeneration.

·       Assessment of cholesterol homeostasis in the living human brain

·       Brain cholesterol and Alzheimer's disease: challenges and opportunities in probe and drug development

·       CYP46A1-mediated cholesterol turnover induces sex-specific changes in cognition and counteracts memory loss in ovariectomized mice

Thanks to funding from the Medical Research Council (MR/Z505730/1) and the Michael J Fox Foundation we have investigated how cholesterol metabolism can change in motor neuron disease and Parkinson’s disease. Interestingly, brain cholesterol metabolism in both disorders is disturbed but in different ways.

A Sterolomic Atlas of Mouse Brain

Based on earlier work funded by the Biotechnology and Biological Sciences Research Council (BB/N015932/1)

·       Visualizing Cholesterol in the Brain by On-Tissue Derivatization and Quantitative Mass Spectrometry Imaging

·       Localization of sterols and oxysterols in mouse brain reveals distinct spatial cholesterol metabolism

and in collaboration with the University of Edinburgh and Aspect Analytics in Belgium we have constructed, using mass spectrometry imaging, a neurosterol and neurosteroid atlas of mouse brain. This work was funded by the Medical Research Council (BB/T018542/1) and the atlas now is freely available.

Lipid Maps

LIPID Metabolites And Pathways Strategy (LIPID MAPS®) is a multi-institutional supported website and database that provides access to a large number of globally used lipidomics resources. I am a member of the  Operational and Management Group and  Nomenclature Group of Lipid Maps.

·       LIPID MAPS: Powering discovery in lipidomics.

·       LIPID MAPS: update to databases and tools for the lipidomics community.

·       Update on LIPID MAPS classification, nomenclature, and shorthand notation for MS-derived lipid structures.