Yuqin Dai

All Publications

• Patient-derived colon epithelial organoids reveal lipid-related metabolic dysfunction in pediatric ulcerative colitis. Nature communications Ojo, B. A., Zhu, Y., Heo, L., Fox, S. R., Qiao, Y., Waddell, A., Moreno-Fernandez, M. E., Gibson, M., Tran, T., Dunn, A. L., Elknawy, E. I., Saini, N., López-Rivera, J. A., Divanovic, S., Dai, Y., de Jesus Perez, V. A., Rosen, M. J. 2025; 16 (1): 11026

  Abstract

  Ulcerative colitis (UC) is associated with epithelial metabolic derangements which exacerbate gut inflammation. Here, we develop colon organoid (colonoid) lines from pediatric patients with endoscopically active UC, inactive UC, and those without intestinal inflammation to interrogate functional metabolic differences in the colon epithelia. We demonstrate that active UC colonoids exhibit hypermetabolic features and cellular stress, specifically during differentiation. Hypermetabolism in active UC colonoids is driven, in part, by increased proton leak, and excess lipid accumulation. Active UC colonoids exhibit heightened activation of the master lipid regulator PPAR-α and its transcriptional pathways. Pharmacological PPAR-α inhibition limits lipid accumulation, induces a metabolic shift towards glucose utilization, suppresses hypermetabolism, and reduces chemokine secretion and cellular stress markers. Collectively, our findings identify lipid-related metabolic dysfunction as a key pathologic feature of the pediatric UC epithelium and highlight the potential of patient-derived colonoids as a preclinical model for evaluating epithelial-targeted therapies addressing this dysfunction.

  View details for DOI 10.1038/s41467-025-65988-2

  View details for PubMedID 41372139

  View details for PubMedCentralID PMC12695892

• ApoE is Secreted as a Lipid Nanoparticle by Mammalian Cells: Implications for Alzheimer's Disease Pathogenesis. Biochemistry Hernandez Arriaza, R., Reil, D., Fatuzzo, N., Fu, M., Dai, Y., Fernandez Martinez, D., Jiang, H., Holtzman, D. M., Greicius, M. D., Khosla, C. 2025

  Abstract

  The brain is the most cholesterol-rich organ in the body, and ApoE is the main lipid carrier protein in the brain. Although very little, if any, ApoE exists in its apoprotein form in physiological fluids, recombinant ApoE is typically prepared in a lipid-free state to study its physiological functions. We describe a lipid nanoparticle (LNP) form of ApoE as a primary extracellular product of the eukaryotic protein export system. Whereas the apoprotein is the dominant secreted product when the APOE gene is overexpressed in mammalian cells, an LNP form of ApoE is also observed. The LNP form is, however, the major secreted product from unmodified CCF-STTG1 astrocytoma cells. The C-terminal domain of ApoE plays a key role in LNP biosynthesis as the ApoE3 W210* truncation mutant is secreted without lipidation. Secreted ApoE LNPs are markedly better substrates than the apoprotein itself for further growth via the action of ATP-dependent lipid pumps. Compared to ApoE3 or the Alzheimer's disease-protective ApoE2 variant, the recovered yield of the LNP form of the disease-predisposing ApoE4 variant is higher. Intriguingly, the LNP yield of the rare disease-protective R251G variant of ApoE4 is comparable to that of ApoE3 and ApoE2. Analogous to the well-documented intracellular biosynthesis of ApoB-containing LNPs, the biogenesis and pathophysiological relevance of the LNP form of ApoE warrant further investigation.

  View details for DOI 10.1021/acs.biochem.5c00503

  View details for PubMedID 41134549

• Cell State-Driven Metabolic Dependency in Small Cell Lung Cancer Kim, J. W., Bebber, C. M., Dai, Y., Bopp, S., Edenhofer, A., Li, A. M., Drainas, A. P., Rosner, T., Berning, L., Yang, M., Leak, L. B., Shrestha, B., Abdallah, A. T., Olivos, H. J., Baron, M., Nguyen, T., Shue, Y., Nishiga, Y., Chaikovsky, A. C., Li, Y., Kang, Y. P., Denicola, G. M., Dixon, S. J., Frezza, C., Ye, J., von Karstedt, S., Sage, J. ELSEVIER SCIENCE INC. 2025

  View details for Web of Science ID 001634549500026

• Plasma lipids as novel biomarker of non-arteritic anterior ischemic optic neuropathy Alkhabaz, A., Kaushal, K., Ren, Y., Modgil, S., Pujari, R., Zhang, J., Zhu, P., Fu, M., Dai, Y., Liao, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2025

  View details for Web of Science ID 001560033700010

• A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites. Cell Moya-Garzon, M. D., Wang, M., Li, V. L., Lyu, X., Wei, W., Tung, A. S., Raun, S. H., Zhao, M., Coassolo, L., Islam, H., Oliveira, B., Dai, Y., Spaas, J., Delgado-Gonzalez, A., Donoso, K., Alvarez-Buylla, A., Franco-Montalban, F., Letian, A., Ward, C. P., Liu, L., Svensson, K. J., Goldberg, E. L., Gardner, C. D., Little, J. P., Banik, S. M., Xu, Y., Long, J. Z. 2024

  Abstract

  β-Hydroxybutyrate (BHB) is an abundant ketone body. To date, all known pathways of BHB metabolism involve the interconversion of BHB and primary energy intermediates. Here, we identify a previously undescribed BHB secondary metabolic pathway via CNDP2-dependent enzymatic conjugation of BHB and free amino acids. This BHB shunt pathway generates a family of anti-obesity ketone metabolites, the BHB-amino acids. Genetic ablation of CNDP2 in mice eliminates tissue amino acid BHB-ylation activity and reduces BHB-amino acid levels. The most abundant BHB-amino acid, BHB-Phe, is a ketosis-inducible congener of Lac-Phe that activates hypothalamic and brainstem neurons and suppresses feeding. Conversely, CNDP2-KO mice exhibit increased food intake and body weight following exogenous ketone ester supplementation or a ketogenic diet. CNDP2-dependent amino acid BHB-ylation and BHB-amino acid metabolites are also conserved in humans. Therefore, enzymatic amino acid BHB-ylation defines a ketone shunt pathway and bioactive ketone metabolites linked to energy balance.

  View details for DOI 10.1016/j.cell.2024.10.032

  View details for PubMedID 39536746

• Multiomics Analysis Illuminates the Molecular Basis of Autosomal Dominant Optic Disc Drusen Kaushal, K., Liu, L., Patel, H., Kumar, A., Pugazhendhi, S., Oses-Prieto, J. A., Shariati, M., Dai, Y., Burlingame, A., Liao, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2024

  View details for Web of Science ID 001312227702009

• Tachycardia-induced metabolic rewiring as a driver of contractile dysfunction. Nature biomedical engineering Tu, C., Caudal, A., Liu, Y., Gorgodze, N., Zhang, H., Lam, C. K., Dai, Y., Zhang, A., Wnorowski, A., Wu, M. A., Yang, H., Abilez, O. J., Lyu, X., Narayan, S. M., Mestroni, L., Taylor, M. R., Recchia, F. A., Wu, J. C. 2023

  Abstract

  Prolonged tachycardia-a risk factor for cardiovascular morbidity and mortality-can induce cardiomyopathy in the absence of structural disease in the heart. Here, by leveraging human patient data, a canine model of tachycardia and engineered heart tissue generated from human induced pluripotent stem cells, we show that metabolic rewiring during tachycardia drives contractile dysfunction by promoting tissue hypoxia, elevated glucose utilization and the suppression of oxidative phosphorylation. Mechanistically, a metabolic shift towards anaerobic glycolysis disrupts the redox balance of nicotinamide adenine dinucleotide (NAD), resulting in increased global protein acetylation (and in particular the acetylation of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase), a molecular signature of heart failure. Restoration of NAD redox by NAD+ supplementation reduced sarcoplasmic/endoplasmic reticulum Ca2+-ATPase acetylation and accelerated the functional recovery of the engineered heart tissue after tachycardia. Understanding how metabolic rewiring drives tachycardia-induced cardiomyopathy opens up opportunities for therapeutic intervention.

  View details for DOI 10.1038/s41551-023-01134-x

  View details for PubMedID 38012305

  View details for PubMedCentralID 5336809

• Carnitine octanoyltransferase is important for the assimilation of exogenous acetyl-L-carnitine into acetyl-CoA in mammalian cells. The Journal of biological chemistry Hsu, J., Fatuzzo, N., Weng, N., Michno, W., Dong, W., Kienle, M., Dai, Y., Pasca, A., Abu-Remaileh, M., Rasgon, N., Bigio, B., Nasca, C., Khosla, C. 2022: 102848

  Abstract

  In eukaryotes carnitine is best known for its ability to shuttle esterified fatty acids across mitochondrial membranes for β-oxidation. It also returns to the cytoplasm, in the form of acetyl-L-carnitine (LAC), some of the resulting acetyl groups for post-translational protein modification and lipid biosynthesis. While dietary LAC supplementation has been clinically investigated, its effects on cellular metabolism are not well understood. To explain how exogenous LAC influences mammalian cell metabolism, we synthesized isotope-labeled forms of LAC and its analogs. In cultures of glucose-limited U87MG glioma cells, exogenous LAC contributed more robustly to intracellular acetyl-CoA pools than did β-hydroxybutyrate, the predominant circulating ketone body in mammals. The fact that most LAC-derived acetyl-CoA is cytosolic is evident from strong labeling of fatty acids in U87MG cells by exogenous 13C2-acetyl-L-carnitine. We found that the addition of d3-acetyl-L-carnitine increases the supply of acetyl-CoA for cytosolic post-translational modifications due to its strong kinetic isotope effect on acetyl-CoA carboxylase, the first committed step in fatty acid biosynthesis. Surprisingly, whereas cytosolic carnitine acetyltransferase (CRAT) is believed to catalyze acetyl group transfer from LAC to Coenzyme A, CRAT-/- U87MG cells were unimpaired in their ability to assimilate exogenous LAC into acetyl-CoA. We identified carnitine octanoyltransferase (CROT) as the key enzyme in this process, implicating a role for peroxisomes in efficient LAC utilization. Our work has opened the door to further biochemical investigations of a new pathway for supplying acetyl-CoA to certain glucose-starved cells.

  View details for DOI 10.1016/j.jbc.2022.102848

  View details for PubMedID 36587768