Intestinal absorption of dietary nutrients is an important process contributing to the etiology of multiple metabolic diseases in humans. An animal?s response to a high-fat meal requires coordination between digestive tissues and intestinal microbiota. Enterocytes (EC) are the absorptive cells of the intestine that prepare lipids for circulation to distal tissues in Apolipoprotein B (ApoB)-containing lipoproteins. Sensory enteroendocrine cells (EEC) communicate nutrient information to other cells and tissues via calcium- dependent hormone release. However, the transcriptional and signaling pathways mediating EC and EEC postprandial responses to a high-fat meal are unclear, and how microbiota influence these interactions is unknown. To address these knowledge gaps, our research team has pioneered the zebrafish system for studies of lipid metabolism and host-microbiota interaction. This includes (1) novel methods to image digestive organ lipid uptake, transport and storage, (2) the first reporter line to quantify the size and numbers of ApoB- containing lipoproteins from vanishing small amounts of material, (3) a fluorescent indicator of EEC activity that permits analysis of in vivo real-time responses to dietary nutrients, and (4) methods for cost-efficient gnotobiotic manipulation. Leveraging these tools for high-resolution in vivo imaging only possible in the larval zebrafish, we have uncovered a dynamic integrative pathway underlying EC, EEC, and microbial postprandial responses to dietary lipids. This includes early postprandial interactions in EC between a host transcription factor and the lipoprotein synthesis enzyme pathway, and late postprandial adaptive responses by EEC that are mediated by microbiota. The objective of this proposal is to define the molecular mechanisms underlying these EC and EEC postprandial responses to dietary lipid, and the specific steps controlled by microbiota. We will test the central hypothesis that microbiota promote lipolysis of dietary fat into fatty acids that are absorbed by EC leading to activation of a transcriptional program and synthesis of ApoB-containing lipoprotein particles, which are collectively perceived by EEC to alter their activity. This competitive renewal leverages long-standing partnerships between three field-leading labs with a powerful set of mutant and novel transgenic reporter lines developed during the prior funding period. The expected outcomes of the proposed research are expected to have a significant impact because they are likely to lead to new strategies for rationally manipulating EC, EEC, and microbiota interactions and responses to dietary fat which could be used to reduce incidence and severity of metabolic diseases in humans.
Alterations in fat metabolism contribute to the etiology of multiple metabolic diseases that ultimately accounts for over 30% of mortality worldwide. The proposed research is designed to discover key mechanisms by which intestinal epithelial cells and microbiota respond to high fat diet and is expected to lead to increased understanding and new treatments for human diabetes, cardiovascular, and other metabolic diseases. The proposed research is therefore relevant to the part of NIH?s mission that pertains to developing fundamental new knowledge that will enhance health and reduce the burdens of illness.
|Minchin, James E N; Scahill, Catherine M; Staudt, Nicole et al. (2018) Deep phenotyping in zebrafish reveals genetic and diet-induced adiposity changes that may inform disease risk. J Lipid Res 59:1536-1545|
|Sæle, Øystein; Rød, Kari Elin L; Quinlivan, Vanessa H et al. (2018) A novel system to quantify intestinal lipid digestion and transport. Biochim Biophys Acta Mol Cell Biol Lipids 1863:948-957|
|Quinlivan, Vanessa H; Farber, Steven A (2017) Lipid Uptake, Metabolism, and Transport in the Larval Zebrafish. Front Endocrinol (Lausanne) 8:319|
|Minchin, J E N; Rawls, J F (2017) In vivo imaging and quantification of regional adiposity in zebrafish. Methods Cell Biol 138:3-27|
|Minchin, James E N; Rawls, John F (2017) A classification system for zebrafish adipose tissues. Dis Model Mech 10:797-809|
|Anderson, Jennifer L; Mulligan, Timothy S; Shen, Meng-Chieh et al. (2017) mRNA processing in mutant zebrafish lines generated by chemical and CRISPR-mediated mutagenesis produces unexpected transcripts that escape nonsense-mediated decay. PLoS Genet 13:e1007105|
|Otis, Jessica P; Shen, Meng-Chieh; Quinlivan, Vanessa et al. (2017) Intestinal epithelial cell caveolin 1 regulates fatty acid and lipoprotein cholesterol plasma levels. Dis Model Mech 10:283-295|
|Minchin, James E N; Rawls, John F (2017) Elucidating the role of plexin D1 in body fat distribution and susceptibility to metabolic disease using a zebrafish model system. Adipocyte 6:277-283|
|Quinlivan, Vanessa H; Wilson, Meredith H; Ruzicka, Josef et al. (2017) An HPLC-CAD/fluorescence lipidomics platform using fluorescent fatty acids as metabolic tracers. J Lipid Res 58:1008-1020|
|O'Hare, Elizabeth A; Yang, Rongze; Yerges-Armstrong, Laura M et al. (2017) TM6SF2 rs58542926 impacts lipid processing in liver and small intestine. Hepatology 65:1526-1542|
Showing the most recent 10 out of 23 publications