Ramsey, M. | bioRxiv Science

bioRxiv2023

Changes in Plasma Fatty Acid Abundance Related to Chronic Pancreatitis: A Pilot Study

ObjectivesChronic pancreatitis (CP) is an inflammatory disease that affects the absorption of nutrients like fats. Molecular signaling in pancreatic cells can be influenced by fatty acids (FAs) and changes in FA abundance could impact CP-associated complications. Here, we investigated FA abundance in CP compared to controls and explored how CP-associated complications and risk factors affect FA abundance. MethodsBlood and clinical parameters were collected from subjects with (n=47) and without CP (n=22). Plasma was analyzed for relative FA abundance using gas chromatography and compared between controls and CP. Changes in FA abundance due to clinical parameters were also assessed in both groups. ResultsDecreased relative abundance of polyunsaturated fatty acids (PUFAs) and increased monounsaturated fatty acids (MUFAs) were observed in subjects with CP in a sex-dependent manner. The relative abundance of linoleic acid increased, and oleic acid decreased in CP subjects with exocrine pancreatic dysfunction and a history of substance abuse. ConclusionsPlasma FAs like linoleic acid are dysregulated in CP in a sex-dependent manner. Additionally, risk factors and metabolic dysfunction further dysregulate FA abundance in CP. These results enhance our understanding of CP and highlight potential novel targets and metabolism-related pathways for treating CP.

physiology↗

bioRxiv2022

Overexpression of AMPKγ2 increases AMPK signaling to augment human T cell metabolism and function

T cell-based cellular therapies benefit from a product with reduced differentiation and enhanced oxidative metabolism. Methods to achieve this balance without negatively impacting T cell expansion or impairing T cell function have proven elusive. AMP-activated protein kinase (AMPK) is a cellular energy sensor which promotes mitochondrial health and improves oxidative metabolism. We hypothesized that increasing AMPK activity in human T cells would augment their oxidative capacity, creating an ideal product for adoptive cellular therapies. Lentiviral transduction of the regulatory AMPK{gamma}2 subunit stably enhanced intrinsic AMPK signaling and promoted mitochondrial respiration with increased basal oxygen consumption rates (OCR), higher maximal OCR, and augmented spare respiratory capacity. These changes were accompanied by increased mitochondrial density and elevated expression of proteins involved in mitochondrial fusion. AMPK{gamma}2-transduction also increased T cell glycolytic activity. This combination of metabolic reprogramming enhanced in vitro T cell expansion while promoting memory T cell yield. Finally, when activated under decreasing glucose conditions, AMPK{gamma}2-transduced T cells maintained higher levels of both proliferation and inflammatory cytokine production. Together, these data suggest that augmenting intrinsic AMPK signaling via overexpression of AMPK{gamma}2 can improve the expansion and function of human T cells for subsequent use in adoptive cellular therapies. Key pointsLentiviral Transduction of AMPK{gamma}2 increases oxidative metabolism in human T cells AMPK{gamma}2 transduction enhances in vitro proliferation without inducing exhaustion AMPK{gamma}2-transduced T cells function better under low glucose conditions

immunology↗