Novel Preventative Strategies for metabolic diseases – Personalized Medicine in times of Big data

Abstract: The global epidemic of obesity is paralleled by a massive rise in metabolic-associated steatotic liver disease (MASLD) and cardiovascular disorders (CVD)^. MASLD, the most common liver disease, already affects 30-40% of the western population and is expected to become the primary cause of liver failure in Western nations. The pathophysiological hallmark of MASLD is excess lipid accumulation in the liver. Steatosis is strongly influenced by genetics, and the best established MASLD-related genetic risk variants TM6SF2 rs58542926 (E167K) and PNPLA3 rs738409 (I148M) both lead to increased hepatocellular lipid accumulation. Since hepatic lipid metabolism and plasma lipoprotein metabolism are so tightly interconnected, pharmacological treatment of steatosis may have an impact on plasma lipids, and vice versa. Overexpression of TM6SF2, for example, decreases steatosis by increasing very-low-density lipoprotein (VLDL) secretion and consequently plasma lipid levels; conversely, approved medications that lower low-density lipoprotein (LDL) cholesterol by reducing hepatic VLDL secretion exacerbate hepatic steatosis. This necessitates the development of novel system-level approaches to uncover new therapeutic targets for hepatic steatosis without increasing plasma lipids and thus CVD risk. The ideal target for MASLD therapy would reduce hepatic lipid accumulation and hence the risk of MASLD while having no effect on (or even reducing) serum lipid levels. In my talk, I discuss novel MASLD treatment approaches in the era of digital, personalized medicine.

Biography: My fascination for the intricate interplay between genetics, environment, and hepatic steatosis began during my medical doctoral thesis, which focused on investigating the impact of the Pi*Z mutation in SERPINA1 on liver and fat metabolism. Under the expert guidance of Prof. Pavel Strnad, I delved into the complexities of this subject, sparking my passion for understanding genetic influences on liver health. During my time in Prof. Strnad’s lab, I realized the significance of detailed phenotyping of common genetic variants. As a patient-centric scientist, my primary goal is to provide better diagnostic and treatment options for my patients. I am particularly driven to alleviate the burden of metabolically associated steatotic liver disease (MASLD) and its complications. In pursuit of expanding my expertise in translational clinical research, I made the decision to pursue a Postdoctoral Fellowship in the US after my state exam in December 2019. I sought to focus on biostatistics and data science to complement my knowledge. This led me to join the esteemed group of Professor Rader, Chair of the Department of Genetics, Deputy Director of the Institute of Translational Medicine and Therapeutics (ITMAT), Head of Translational Medicine and Human Genetics, and Principal Investigator at the Penn Medicine Biobank at University of Pennsylvania.

During my postdoctoral work, I engaged in projects centered around exploring common genetic variants and their influence on hepatic lipid metabolism. My ultimate objective was to decipher the molecular signaling pathways related to lipid metabolism that contribute to MASLD. By studying these genetic variants, I aspired to develop interventional strategies to mitigate the major complications associated with MASLD. After three productive years as a postdoc at UPENN, I took the next step in my journey and established my own lab in July 2022. The core focus of my lab is to utilize genetic variants as a foundation for identifying therapeutic targets in metabolic diseases, harnessing the power of big data and artificial intelligence in my research. Through my work, I hope to make meaningful contributions to the understanding and treatment of metabolic diseases, ultimately improving the lives of patients worldwide.

Photo rights: Nordrhein-Westfälische Akademie der Wissenschaften und der Künste | Bettina Engel-Albustin 2022

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