Previous University and Subject: Technical University of Munich, Germany; Nutrition & Biomedicine
Thesis since: 10/2019
Role of PNPLA3 in Macrophages in Metabolic Liver Injury
The Non-alcoholic fatty liver disease (NAFLD) has become one of the most common causes of chronic liver injury globally due to the increase in the prevalence of metabolic syndrome. NAFLD encompasses a spectrum of disorders, starting as benign steatosis with the potential to advance to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma.
Aside from the environmental factors which may influence metabolic syndrome and hence, NAFLD, the propensity to develop the disease seems to differ among ethnic groups, suggesting a potential genetic role. A single nucleotide polymorphism (rs738409; C>G) in the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene encoding the I148M variant confers a heightened risk for NAFLD. The PNPLA3 gene has been suggested to be a lipid droplet-associated protein that has both triglycerides hydrolase and acyltransferase activities.
Most studies implicating PNPLA3 I148M variant to NAFLD development were largely conducted in hepatocytes and hepatic stellate cells although, inflammation orchestrated by infiltrating monocytes and Kupffer cells play an important role in the disease progression. Our preliminary data in human monocytes isolated from peripheral blood of volunteers carrying the PNPLA3 I148M variant show increased levels of pro-inflammatory cytokines and CD16 marker compared to wildtype. At baseline, the variant monocytes release high levels of proinflammatory chemokines and cytokines, suggesting a potential involvement of the PNPLA3 I148M variant in driving systemic and hepatic inflammation. Since NAFLD is a systemic disease, it is imperative to look at the input from other tissues. Dysfunction of adipose tissue has been shown by numerous studies to be a critical factor in the etiology and recurrence of NAFLD as often seen in liver transplant patients. Notwithstanding its immense clinical relevance, the molecular function of the PNPLA3 gene and the mechanistic principle by which its genetic variant disrupts lipid metabolism leading to NAFLD development remain elusive.
To this end, I plan to:
• Explore whether PNPLA3 I148M influences adipose tissue metabolic and inflammatory function.
• Explore the role of PNPLA3 in macrophage lipid metabolism.
• Investigate whether and how the PNPLA3 I148M variant influences monocyte phenotype, migration, differentiation, and macrophage polarization, both in vitro and in animal models of metabolic syndrome related NAFLD.
Innovative aspects: Findings from this project are expected to result in novel mechanistic insights into the role of lipid metabolism in NAFLD including new prognostic and therapeutic strategies targeting PNPLA3.
Methods and Skills:
PCR; Western blot; tissue staining & histology; animal experimentation; cell culture
Fuchs CD, Radun R, Dixon ED, Mlitz V, Timelthaler G, Halilbasic E, Herac M, Jonker JW, Ronda O, Tardelli M, Haemmerle G, Zimmermann R, Scharnagl H, Stojakovic T, Verkade HJ, Trauner M: Hepatocyte-specific deletion of adipose triglyceride lipase (adipose triglyceride lipase/patatin-like phospholipase domain containing 2) ameliorates dietary induced steatohepatitis in mice. Hepatology 75: 125-139, 2022
Nardo AD, Schneeweiss-Gleixner M, Bakail M, Dixon ED, Lax SF, Trauner M: Pathophysiological mechanisms of liver injury in COVID-19. Liver international 41: 20-32, 2021
Dixon, ED, Nardo AD, Claudel T, Trauner M: The role of lipid sensing nuclear receptors (PPARs and LXR) and metabolic lipases in obesity, diabetes and NAFLD. Genes (Basel) 12: 645, 2021
Dixon E, Rabanser I, Dzieciol M, Zwirzitz B, Wagner M, Mann E, Stessl B, SU Wetzels: Reduction potential of steam vacuum and high-pressure water treatment on microbes during beef meat processing. Food Control 106: 106728, 2019