744B Poster - 12. Physiology, metabolism and aging
Friday April 08, 2:00 PM - 4:00 PM

Authors:
Xiaotong Li; Jason Karpac

Affiliation: Department of Molecular and Cellular Medicine, Texas A&M University, College of Medicine, Bryan, TX

Keywords:
b. metabolism; d. intestinal stem cells

Nutrient availability is a major selective force in the evolution of metazoa, and organisms thus need to carefully adapt to nutrient changes in order to promote somatic maintenance and reproduction. This adaptation has also shaped the cellular and molecular mechanisms that underly nutrient-dependent remodeling of tissue function and morphology. Here, we leveraged a meta-analysis of transcriptomics datasets and phylogenomics and discovered that Acbp6 (Acyl-CoA binding protein 6) is a critical regulator of nutrient-dependent tissue remodeling in Drosophila. Acbp6 arose by evolutionary duplication in the Drosophila order, and is uniquely expressed in functionally differentiated enterocytes of the regenerating fly midgut (intestine). We found that Acbp6, which binds Acyl-CoA with high-affinity and thus dictates cellular Acetyl-CoA metabolism, is required for intestinal regrowth after nutrient deprivation (fasting) through adjusting intestinal stem cell (ISC) activation from quiescence. Fasting induces intestine morphological recession, while refeeding promotes intestinal remodeling and growth in Drosophila. Acbp6 expression is induced by fasting, and normalizes after refeeding. However, attenuation of Acbp6 led to abnormal tissue remodeling after fasting, due to uncoordinated regulation of ISC activation and proliferation. Moreover, Acbp6 inhibition also drives aberrant 'switching' of metabolic cycles in enterocytes during nutrient adaptation, which overall impaired Acetyl-CoA production. Decreases in Acetyl-CoA led to attenuation of pan-acetylation of proteins in enterocytes during refeeding and intestinal regrowth. Re-expression of Acbp6 or acetate supplementation can restore pan-acetylation and promote ISC activation from quiescence during nutrient adaptation. Through genetic screening we identified Stat92e, which can be acetylated, as a key regulator of ISC activation from quiescence during refeeding. In enterocytes, Stat92e can govern Upd3 induction during nutrient adaptation, and Upd3 can dictate ISC proliferation and intestinal regrowth. Our data thus define a new regulatory mechanism, shaped by Acyl-CoA metabolism, that is required to adjust stem cell quiescence and activation, and therefore drive tissue remodeling during nutrient adaptation.