The role of the PNPLA3 I148M polymorphism for adipose tissue function in health and disease
Final Report Abstract
Obesity, the metabolic syndrome, and their sequelae represent a major challenge for current and future health care. In this context, molecular mechanisms can have positive or negative effects on the whole organism, depending on whether there is normal weight or obesity, or whether there is nutrient excess or deficiency (e.g. during fasting). There are numerous fasting concepts (e.g. interval fasting), but their exact physiological relationships have not yet been clarified. PNPLA3 is a phospholipase expressed in numerous tissues of the body. A common polymorphism of this enzyme is known to worsen metabolic liver disease in obese individuals. Adipose tissue serves as an energy storage tissue and may also be a source of inflammatory messengers and pro-inflammatory cells in obese individuals. Our aim was to investigate the polymorphism of the phospholipase PNPLA3 in adipose tissue with respect to its relevance in obesity, as well as in nutrient excess or deficiency. We demonstrated that mice carrying the PNPLA3 polymorphism worsened metabolic liver disease. Weight gain is accompanied by redistribution of adipose tissue. We were able to show increased inflammatory cell infiltration into the liver with consecutive damage to the organ and worsening of hepatic fibrosis. We could not detect any effect of the polymorphism on adipocyte metabolism after fasting or feeding. This was equally evident for in vitro experiments as in vivo experiments with short-term food restriction or interval fasting. We then used our experimental data to investigate the effect of fasting or feeding on tumor cell metabolism and their ability to take up substances. We demonstrated that interval fasting selectively enhanced the uptake of nano-carriers in tumor cells and that tumor size was reduced in an in vivo model. In summary, we confirmed a role of PNPLA3 polymorphism in metabolic liver disease, with PNPLA3 appearing to play a secondary role in adipose tissue. This is also true for interval fasting. However, independent of PNPLA3, interval fasting intervention could be helpful in selective drug therapy of tumors according to our results.
Publications
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Intermittent Fasting Primes the Tumor Microenvironment and Improves Nanomedicine Delivery in Hepatocellular Carcinoma. Small, 19(43).
Becker, Svea; Momoh, Jeffrey; Biancacci, Ilaria; Möckel, Diana; Wang, Qingbi; May, Jan‐Niklas; Su, Huan; Candels, Lena Susanna; Berres, Marie‐Luise; Kiessling, Fabian; Hatting, Maximilian; Lammers, Twan & Trautwein, Christian
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Long‐term hypercaloric diet exacerbates metabolic liver disease in PNPLA3 I148M animals. Liver International, 43(8), 1699-1713.
Su, Huan; Haque, Madhuri; Becker, Svea; Edlund, Karolina; Duda, Julia; Wang, Qingbi; Reißing, Johanna; Marschall, Hanns‐Ulrich; Candels, Lena S.; Mohamed, Mohamed; Sjöland, Wilhelm; Liao, Lijun; Drexler, Stephan A.; Strowig, Till; Rahnenführer, Jörg; Hengstler, Jan G.; Hatting, Maximilian & Trautwein, Christian
