Molecular investigation of mechanosensing mediated lipid regulation in health and disease

Summary

Dr Lichtenstein recently demonstrated a novel link between how the blood flow is sense in the liver vasculature and hepatic lipid homeostasis. The PhD project Dr Lichtenstein proposes will investigate further this novel research concept, in health and disease. The project will be articulated between key biochemistry and molecular techniques in the school of Food Science and Nutrition in the University of Leeds, and in collaboration with the Faculty of Medicine.

Non-Alcoholic Fatty Liver Disease (NAFLD) affects 1 in 3 people in the UK¹. Amongst metabolic diseases, NAFLD is independently associated to cardiovascular diseases (CVD) and CVD is the most common cause of death in NAFLD patient². Given the rapidly growing global burden of NAFLD worldwide, the scientific community increase efforts and sharpen tools to diagnose it in early stages, but many aspects of the biology linking NAFLD and CVD are unclear. Fatty liver is an increasing major unsolved problem linked to cardiovascular disease, where endothelial cells are key. An important missing aspect is understanding of how mechanical forces from blood flow affect hepatic lipid homeostasis.

Endothelial cells, cells lining the blood vessels, sense mechanical forces from blood flow in the body and we and others have shown the importance of Liver Sinusoidal Endothelial Cells (LSECs) in liver functions^4,5,6. Dr Lichtenstein and collaborators recently demonstrated the unique role of one of the mechanical and flow sensors expressed in LSECs, PIEZO1 (PIEZO1), in the control of lipid homeostasis⁷, using inducible endothelial PIEZO1 knock out mice. Using mouse liver perfusion approach, we showed that physiological flow rate changes in the entrance of the liver, stimulates endothelial PIEZO1, which promotes phosphorylation of nitric oxide synthase 3 (NOS3), that in turn supresses Cyp7a1, the rate limiting enzyme in cholesterol to bile acid conversion⁷. It was the first time the link between flow induced mechanosensing and hepatic lipid homeostasis has been made.

Bile acids are formed by the liver and actively reabsorbed by the small intestine entering the enterohepatic circulation⁸. Bile acids concentration and species change in our model, suggesting blood flow sensing is regulating bile acids synthesis and lipid absorption. Another important finding was an increase cholesterol excretion, involving Low density lipoprotein receptor (LDLr) upregulation in the distal part of the small intestine.

Aim: The PhD project will investigate the underlying pathway and regulation of cholesterol metabolism on organ perfusion model, ex vivo, in the context of dietary lipids relevant to nutrition.

Project

A multidisciplinary approach, employing biochemistry, metabolic and in vivo/ex-vivo techniques, will be utilized to investigate the flow dependent impact on lipid homeostasis in the enterohepatic circulation.
The PhD student will enable the investigation using complementary approaches: lipidomics (LC-MS, Prof Lee Roberts, LICAMM), western blot (protein regulation), histology (cryosection on tissues) and transcriptomics (RNAseq and real time Q-PCR).

References

[1] NHS-web-site. Non-alcoholic fatty liver disease (NAFLD). https://www.nhs.uk/condition /non-alcoholic-fatty-liver-disease/(2020).

[2] Targher, G., et al.. J Hepatol 65, 589-600, (2016).

[3] Poisson, J. et al. J Hepatol 66, 212-227, (2017).

[4] Caolo, V. et al. Elife 9, (2020).

[5] Li, J. et al. Nature 515, 279-282, (2014).

[6] Hilscher, M. B. et al. Gastroenterology 157, 193-209, (2019).

[7] Lichtenstein et al. Science Advances, In Press.

[8] Hofman A.F. Arch Intern Med 22, 2647-2658, (1999).

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