Exploring new therapeutic targets in cardiometabolic disease

This proposal has direct relevance to major health challenges in Qatar and has high translational potential. Disturbances in lipid metabolism are at the core of several major health issues facing modern society, including cardiovascular disease (CVD), obesity and type 2 diabetes (T2D). CVD is the leading cause of death from non-communicable diseases in Qatar and the incidence of heart attacks and strokes among young Qataris is one of the highest in the world. According to the Qatar Biobank (QBB), the prevalence of obesity and T2D in Qatar is very high, with an estimated 40% and 20% of the population being obese and/or diabetic, respectively. Thus, Qatar is facing a cardiometabolic health crisis, with wide-ranging health, social and economic consequences. The current proposal aims to explore and validate new therapeutic targets in cardiometabolic disease. Members of the SREBP family of transcription factors control cholesterol and lipid metabolism and are intimately linked to human metabolic disease. The activity of the SREBP transcription factors is tightly controlled by cholesterol and insulin signaling. By working as an SREBP chaperone and cholesterol sensor, the SCAP protein plays a central role in controlling the SREBP pathway. The SREBP pathway is a major target for cholesterol and lipid lowering therapies. Globally, over 250 million people take statins to reduce their LDL-cholesterol levels, and the cholesterol-lowering action of these drugs is dependent on SREBP and SCAP function. In addition, SREBP-dependent lipid synthesis contributes to the development of insulin resistance in diabetic patients, because of the selective insulin resistance often seen in the liver of patients with T2D. Thus, the signals and factors controlling SREBP function are very relevant to human disease. The current proposal is focused on elucidating the mechanisms involved in regulating the function of SREBP and SCAP. Thus, our research could impact on major health issues by identifying novel therapeutic targets. Animal models are powerful tools to study lipid metabolism, but are not ideal for mechanistic work. In addition, the regulation of lipid and lipoprotein metabolism is not fully conserved between rodents and humans. Because of the limited supply of healthy primary human cells, lipid metabolism has not been studied in great detail in normal human cells and there is an urgent need to develop such cell models. Thus, the aim of WP1 is to establish an in vitro platform consisting of physiologically relevant non-transformed human cells. These types of models may become an important complement to animal and human/patient studies, and may prove especially valuable when translating observations made in animal models to a human setting, and during drug development. In this proposal, these cell models will be used to explore potential drug targets associated with the SREBP pathway. This work package will benefit from the knowledge and reagents generated by an existing NPRP proposal led by Dr. Essam Abdelalim at the Qatar Biomedical Research Institute (QBRI) (NPRP10-1221-160041). During this QNRF-funded project, Dr. Abdelalim’s group has used stem cell technologies to generate mature hepatocytes from cells obtained from Qatari patients, both healthy subjects and patients suffering from metabolic disease. Dr. Abdelalim is a PI on this proposal and the hepatocytes generated in his laboratory will be used to study SREBP-dependent lipid metabolism. To our knowledge, this will be the first time the SREBP pathway is analyzed in human cell models with such translational potential. Our work has established that the active forms of the SREBP transcription factors are regulated by various post-translational modifications, especially serine/threonine (S/T) phosphorylation, which in turn modulate their activity and stability. Phosphorylation of specific residues induces the degradation of SREBP in a manner dependent on the ubiquitin ligase Fbw7. On the other hand, phosphorylation of a separate set of S/T residues in SREBP attenuates its Fbw7-dependent degradation. Thus, by regulating the phosphorylation of the active transcription factors, cells are able to control the strength and duration of SREBP-dependent transcription in response to specific signaling events. The phosphorylation-dependent regulation of SREBP could be an attractive target for lipid-lowering therapies in CVD, obesity and diabetes. However, before this is possible, we need to obtain a better understanding of the molecular mechanisms involved. WP2 is focused on the elucidation of these mechanisms in physiologically relevant human cell models. We recently completed a number of large shRNA screens targeting protein kinases, protein phosphatases and ubiquitin ligases. In one of these screens, we identified a putative ubiquitin ligase, SCAP regulator-1 (SCR1), as a novel regulator of SCAP. Since SCAP is of critical importance for the function of the entire SREBP pathway, SCR1 has the potential to control both cholesterol and fatty acid/triglyceride metabolism. Thus, the activity of SCR1 could represent a novel therapeutic target in human metabolic disease. WP3 is focused on elucidating the mechanisms of SCR1-mediated regulation of SCAP and its impact on SREBP-dependent lipid metabolism.

Hamad Bin Khalifa University (HBKU)