Molecular investigation of mechanosensing mediated lipid regulation in health and disease

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.

<p>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.</p> <p>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.</p> <p>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.</p> <p>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.</p> <p><strong>Project</strong></p> <p>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. <br /> 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).</p> <p><strong>References</strong></p> <p>[1] NHS-web-site. Non-alcoholic fatty liver disease (NAFLD). https://www.nhs.uk/condition /non-alcoholic-fatty-liver-disease/(2020).</p> <p>[2] Targher, G., et al.. J Hepatol 65, 589-600, (2016).</p> <p>[3] Poisson, J. et al. J Hepatol 66, 212-227, (2017).</p> <p>[4] Caolo, V. et al. Elife 9, (2020).</p> <p>[5] Li, J. et al. Nature 515, 279-282, (2014).</p> <p>[6] Hilscher, M. B. et al. Gastroenterology 157, 193-209, (2019).</p> <p>[7] Lichtenstein et al. Science Advances, In Press.</p> <p>[8] Hofman A.F. Arch Intern Med 22, 2647-2658, (1999).<br />  </p>

<p>Formal applications for research degree study should be made online through the <a href="https://www.leeds.ac.uk/research-applying/doc/applying-research-degrees">University's website</a>. Please state clearly in the research information section that the research degree you wish to be considered for is <strong>Molecular investigation of mechanosensing mediated lipid regulation in health and disease</strong> as well as <a href="https://environment.leeds.ac.uk/food-nutrition/staff/12764/dr-laeticia-lichtenstein">Dr Laeticia Lichtenstein</a> as your proposed supervisor.</p> <p>If English is not your first language, you must provide evidence that you meet the University's minimum English language requirements (below).</p> <p><em>As an international research-intensive university, we welcome students from all walks of life and from across the world. We foster an inclusive environment where all can flourish and prosper, and we are proud of our strong commitment to student education. Across all Faculties we are dedicated to diversifying our community and we welcome the unique contributions that individuals can bring, and particularly encourage applications from, but not limited to Black, Asian, people who belong to a minority ethnic community, people who identify as LGBT+ and people with disabilities. Applicants will always be selected based on merit and ability.</em></p>

Applicants to research degree programmes should normally have at least a first class or an upper second class British Bachelors Honours degree (or equivalent) in an appropriate discipline. The criteria for entry for some research degrees may be higher, for example, several faculties, also require a Masters degree. Applicants are advised to check with the relevant School prior to making an application. Applicants who are uncertain about the requirements for a particular research degree are advised to contact the Postgraduate Research Admissions team prior to making an application.

The minimum English language entry requirement for research postgraduate research study is an IELTS of 6.5 overall with at least 6.0 in each component (reading, writing, listening and speaking) or equivalent. The test must be dated within two years of the start date of the course in order to be valid. Some schools and faculties have a higher requirement.

<p><strong>Self-Funded or externally sponsored students are welcome to apply.</strong></p> <p>UK – The <a href="https://phd.leeds.ac.uk/funding/209-leeds-doctoral-scholarships-2022">Leeds Doctoral Scholarships</a> and <a href="https://phd.leeds.ac.uk/funding/234-leeds-opportunity-research-scholarship-2022">Leeds Opportunity Research Scholarship</a> are available to UK applicants (will reopen from October 2024 for October 2025 entry). <a href="https://phd.leeds.ac.uk/funding/60-alumni-bursary">Alumni Bursary</a> is available to graduates of the University of Leeds.</p> <p>Non-UK – <a href="https://phd.leeds.ac.uk/funding/48-china-scholarship-council-university-of-leeds-scholarships-2021">The China Scholarship Council - University of Leeds Scholarship</a> is available to nationals of China (will reopen from October 2024 for October 2025 entry). The <a href="https://phd.leeds.ac.uk/funding/73-leeds-marshall-scholarship">Leeds Marshall Scholarship</a> is available to support US citizens. <a href="https://phd.leeds.ac.uk/funding/60-alumni-bursary">Alumni Bursary</a> is available to graduates of the University of Leeds.<br /> Important:  Any costs associated with your arrival at the University of Leeds to start your PhD including flights, immigration health surcharge/medical insurance and Visa costs are not covered under this studentship.</p> <p>Please refer to the <a href="https://www.ukcisa.org.uk/">UKCISA website</a> for information regarding Fee Status for Non-UK Nationals.<br />  </p>

<p>For further information please contact Dr Laeticia Lichtenstein: <a href="mailto:L.Lichtenstein@leeds.ac.uk">L.Lichtenstein@leeds.ac.uk</a>. </p>