Metabolism
Abstract
Regulatory T cells (Tregs) maintain immune tolerance through mechanisms tightly coupled to cellular metabolism. Whereas glycolysis supports Treg migration, lipid metabolism sustains their suppressive phenotype. Here, we identify the sterol regulatory element–binding protein 1c (SREBP1c) as a central regulator of Treg immunobiology. Tregs from Srebp1c-deficient mice displayed impaired suppressive function, reduced frequencies in circulation and lymphoid tissues, and diminished expression of functional markers. These defects stemmed from intrinsic metabolic rewiring rather than systemic alterations, as both ex vivo Tregs (CD4+CD25hiFoxP3+) and in vitro-derived Tregs lacking Srebp1c were shifted toward glycolysis. Integrated transcriptomic and lipidomic analyses revealed that Srebp1c-deficient Tregs exhibited defective phospholipid remodeling, with an accumulation of lysophosphatidylcholines over phosphatidylcholines, which we attributed to enhanced cytosolic phospholipase A2 (cPLA2α) activity and disruption of the Lands cycle. Altered lipid composition impaired adenosine-mediated immunosuppression by reducing CD73 expression and extracellular adenosine generation. Accordingly, pharmacological inhibition of cPLA2α restored adenosine signaling, CD73 expression, and Treg suppressive capacity. Thus, by preserving phospholipid homeostasis, SREBP1c functions as an immunometabolic checkpoint that links lipid metabolism to adenosine-dependent Treg suppression.
Authors
Fabrizia Bonacina, Claudio Procaccini, Marta Iaia, Arianna Moretti, Monika Svecla, Silvia Pedretti, Jeroen F.J. Bogie, Giovani Battista Vingiani, Annalisa Moregola, Francesca Genova, Claudia Russo, Giusy De Rosa, Claudia La Rocca, Giada Mondanelli, Marco Gargaro, Nico Mitro, Giuseppe Matarese, Giuseppe Danilo Norata
Abstract
Antimetabolites, chemotherapy targeting nucleotide biosynthesis, are among the oldest and most widely used cancer treatments, yet resistance remains a daunting barrier, especially in the fight against B cell lymphomas. However, the underlying mechanisms of this resistance have long remained elusive. Using an innovative, integrated omics approach, we unexpectedly identified that the accumulation of dipeptides and upregulation of the dipeptide transporter SLC15A3 underlie resistance to nucleotide deficiency in a Myc-driven large B cell lymphoma mouse model. A similar mechanism occurred after long treatment of human B cell lymphoma cells with the chemotherapeutic purine synthesis inhibitor 6-mercaptopurine (6MP). Mechanistically, we demonstrated that dipeptides containing essential amino acids activated the growth and survival mTOR complex 1 (mTORC1) signaling pathway. Notably, SLC15A3 specifically interacted with mTOR on the lysosome, boosting mTORC1 activity selectively in resistant lymphoma cells but not in parental cancer cells. Silencing SLC15A3 diminished mTORC1 activity and restored resistant lymphoma sensitivity to 6MP. Strikingly, resistant lymphomas, but not primary tumors, exhibited heightened sensitivity to the clinical mTOR inhibitor, rapamycin, in culture and in vivo. We extended these findings in human lymphoma biopsies, which revealed increased SLC15A3 expression following antimetabolite therapy. Together, our study uncovered a metabolic adaptation that fuels cancer resistance to nucleotide deficiency and positions the mTORC1 inhibitor, rapamycin, as a potential therapeutic strategy for transforming the management of chemotherapy-resistant lymphomas.
Authors
Haojun Yang, Vincenzo Andrea Zingaro, Kevin Boardman, Ashish Noronha, Ekin Guney, Lingru Xue, Saishma Hoigebazar, Isabelle Liu, Sohit Miglani, Siyu Chen, Hieu Vu, Kwun Wah Wen, Hao G. Nguyen, Hani Goodarzi, Ralph J. DeBerardinis, Davide Ruggero
Abstract
BACKGROUND Obesity and weight loss in adults have been associated with distinct metabolome and gut microbiome features, but the extent to which those associations apply to adolescent stages remain unclear.METHODS The Pediatric Obesity Microbiome and Metabolism Study (POMMS) enrolled 220 adolescents aged 10–18 with severe obesity (OB) and 67 individuals who were healthy weight controls (HWCs). Blood, stool, and clinical measures were collected at baseline and after a 6-month obesity intervention for the OB group. Metabolomic profiling in serum using targeted quantitative mass spectrometry and microbiome profiling in stool were performed, and those features were assessed for associations with BMI, insulin resistance, and inflammation. Fecal microbiome transplants (FMT) were performed on germ-free mice using samples from both groups to assess effects on weight gain and metabolic pathways.RESULTS Adolescents with OB exhibited higher serum branched-chain amino acid (BCAA) but lower branched-chain ketoacid (BCKA) levels compared with HWC. This pattern was sex- and age-dependent and differed from adults with obesity who show elevated levels of both BCAA and BCKA. Longitudinal analysis identified metabolic and microbial features correlated with changes in health measures during the intervention. The fecal microbiomes of adolescents with OB and HWC had similar diversity but differed in membership and functional potential. FMT from both OB and HWC donors had similar effects on mouse body weight, but specific taxa were linked to weight gain in recipients of FMT.CONCLUSION Adolescents with OB have unique metabolomic adaptations and microbiome signatures compared with their HWC counterparts and adults with OB.TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03139877 (Observational Study) and NCT02959034 (Repository).FUNDING SUPPORT American Heart Association Grants: 17SFRN33670990, 20PRE35180195; National Institute of Diabetes and Digestive and Kidney Diseases Grant: R24-DK110492.
Authors
Jessica R. McCann, Chengxin Yang, Nathan A. Bihlmeyer, Runshi Tang, Tracy Truong, Wei Zhou, Jie An, Jayanth Jawahar, Olga Ilkayeva, Michael J. Muehlbauer, Zhengzheng Hu, Holly Kloos Dressman, Lisa Poppe, Joshua A. Granek, Jason W. Arnold, Lawrence A. David, Julia Oh, Pixu Shi, Pinar Gumus Balikcioglu, Svati H. Shah, Sarah C. Armstrong, Christopher B. Newgard, Patrick C. Seed, John F. Rawls
Abstract
Cholesterol overload contributes to metabolic dysfunction–associated steatohepatitis (MASH) progression. One major pathway that limits hepatic cholesterol accumulation is export via VLDL secretion. While sterol regulatory element–binding protein (SREBP) activity is suppressed by insulin-induced gene 1 (INSIG1) under high sterol conditions, VLDL secretion nonetheless persists to prevent lipotoxicity and liver injury, presenting an unresolved paradox in cholesterol sensing and lipoprotein export. Here, we identified a cholesterol-responsive interaction between nuclear factor erythroid 2 related factor-1 (NFE2L1) and INSIG1 that preserved cholesterol homeostasis by sustaining VLDL secretion. Liver-specific NFE2L1 deletion elevated INSIG1 abundance, suppressed SREBP1 activation, and impaired VLDL secretion, leading to hepatic cholesterol accumulation and liver injury. Mechanistically, NFE2L1 bound to INSIG1 via its N-terminal homology box 2 (NHB2) domain; free cholesterol strengthened this interaction to promote INSIG1 degradation, thereby enabling SREBP1 activation and VLDL export. In NFE2L1-deficient mice, WT NFE2L1, but not a mutant NFE2L1 form unable to interact with INSIG1 (NHB2-deleted mutant, ΔNHB2), restored SREBP1 activity and VLDL secretion. Lipidomics analysis revealed that NFE2L1 deficiency reduced serum triglyceride composition, which was restored exclusively by WT NFE2L1. In a murine MASH model, NFE2L1 overexpression activated SREBP1/2, lowered hepatic cholesterol, and attenuated liver injury, inflammation, and fibrosis, without elevating atherogenic lipoproteins owing to compensatory LDL receptor upregulation. Together, these findings explain how VLDL secretion capacity was maintained under cholesterol excess and identify the NFE2L1/INSIG1 axis as a sterol-responsive safeguard for hepatic lipid homeostasis and a potential therapeutic target for MASH.
Authors
Shijun Deng, Jessica E. Freed, Grace Y. Lee, Gizel Askin, Zhe Cao, Özgür Cakici, Bo Yuan, Sheng Tony Hui, Karen E. Inouye, Isabel Graupera, Gökhan S. Hotamışlıgil
Abstract
Authors
Abdualrahman Mohammed Abdualkader, Xiaobei Li, Yiming Yin, Chenhao Bai, Parisa Pourfarziani, Jiaheng Guan, Sora Kwon, Kyoung-Han Kim, Rami Al Batran
Abstract
The inflammatory response resulting from the abnormal accumulation of metabolites has been implicated in the pathogenesis of organ fibrosis; however, its role and underlying mechanisms in renal fibrosis remain unclear. In this study, we observed a negative correlation between fumarate hydratase (FH) expression and the degree of renal fibrosis. Loss of FH function was associated with heightened inflammation and exacerbated tubulointerstitial damage in the kidney. Moreover, FH deficiency aggravated fibrosis in both the liver and lungs. Mechanistically, the depletion of FH in renal tubular cells led to fumarate accumulation. Fumarate directly succinated A-kinase anchoring protein 12 at cysteine 670, thereby diminishing its capacity to inhibit the activity of protein kinase Cζ (PKCζ). This process exacerbated renal inflammation and fibrosis by activating the downstream PKCζ/NF-κB and PKCζ/β-catenin pathways. Additionally, the upregulation of FH through adeno-associated virus 2/9-mediated FH overexpression markedly mitigated renal inflammation and fibrosis. These findings highlighted the important role of fumarate accumulation in the advancement of renal fibrosis, supporting FH as a potential therapeutic target in renal fibrosis.
Authors
Shuai Sun, Xu-yang Yan, Yu-hang Dong, Jian-min You, Zhen-yu Guo, Dong-xue Lv, Shuai-shuai Xie, Rui Hou, Xiang-yu Li, Ju-tao Yu, Xiao-yu Shen, Jie Wei, Zhen-yu Song, Zi-qi Chen, Yun-long Zhu, Xing-xin Xu, Juan Jin, Jia-gen Wen, Hao Wang, Xiao-ming Meng, Wei Wang
Abstract
Most mitochondrial proteins are nuclear encoded, translated in the cytosol, and imported into the mitochondria. Through gene expression analysis and functional assays, we demonstrated that mitochondrial protein import is increased in acute myeloid leukemia (AML) cells compared to normal hematopoietic cells. Increased mitochondrial protein import was positively correlated with increased mitochondrial unfolded protein response (UPRmt), a stress activated pathway of mitochondrial proteases and chaperones that maintains protein solubility and prevents the formation of toxic aggregates. The UPRmt protease LONP1 (Lon Peptidase 1) was upregulated in AML and positively correlated with increased mitochondrial protein import and UPRmt. Genetically or chemically inhibiting the LONP1 ATPase domain induced mitochondrial protein aggregation and selectively killed AML cells with high LONP1 expression while sparing AML cells with low LONP1 expression and normal hematopoietic cells in vitro and in vivo. Thus, we uncovered a critical role of the UPRmt protease LONP1 in buffering stress from mitochondrial protein import in AML.
Authors
Matthew Tcheng, Veronique Voisin, Geethu Emily Thomas, Anastasija A. Piric, Marcela Gronda, Rose Hurren, Dakai Ling, Yongran Yan, Lan Xin Zhang, Yue Feng, Ali Chegini, Nathan Duong, Ross S. Mancini, Stefan Quinn W. Currie, Zaynab Mamai, Brady Stock, Shahbaz Khan, Yulia Jitkova, Chaitra Sarathy, Edward Ayoub, Po Yee Mak, Andrea Arruda, Thomas Kislinger, Mark Reed, Bing Z. Carter, Michael Andreeff, Steven M. Kornblau, Mark D. Minden, Siavash Vahidi, Aaron D. Schimmer
Abstract
Androgen deprivation therapy (ADT), a cornerstone of advanced prostate cancer treatment, effectively suppresses androgen signaling but frequently induces systemic metabolic dysregulation. Here, we delineate an unrecognized intestinal steroid/bile acid regulatory axis that mechanistically links androgen suppression to extratumoral metabolic aberrations. HSD3B1 is the most common inherited link to prostate cancer mortality and mediates its effects by regulating steroid metabolism. Integrated metabolomic profiling of patients undergoing ADT revealed a rapid genotype-associated reduction in circulating bile acids, most pronounced in carriers of the adrenal-permissive HSD3B1 (1245C) allele. Surprisingly, analyses in human intestinal tissue and mechanistic investigations in in vitro models identified the terminal ileum as a unique site of HSD3B1 and SLC10A2 (ASBT) coexpression, where catalytically active 3βHSD1 is transcriptionally governed by liver receptor homolog-1 (LRH-1). Pharmacologic or genetic LRH-1 inhibition coordinately suppressed HSD3B1 and SLC10A2 expression and function, while inducing adaptive HSD11B2 upregulation and enhanced glucocorticoid inactivation. This LRH-1–dependent regulatory program persisted independently of androgen and glucocorticoid receptor signaling under in vitro conditions modeling androgen deprivation. These findings establish LRH-1 as a central integrator of intestinal steroidogenesis and bile acid transport and implicate the LRH-1/HSD3B1/SLC10A2 network as a mechanistic driver of ADT-associated metabolic disturbances and a potential target for therapeutic intervention.
Authors
Nikou Fotouhi, Robert Diaz, Mohammad Alyamani, Yoon-Mi Chung, Gail West, Pranab K. Mukherjee, Alireza Abdshah, Robert A. Burgess, Samreen Jatana, Rana R. McKay, Florian Rieder, Mary-Ellen Taplin, Nima Sharifi
Abstract
Interrupting glucagon signaling decreases gluconeogenesis and the fractional extraction of amino acids by liver from blood, resulting in lower glycemia. The resulting hyperaminoacidemia stimulates α cell proliferation and glucagon secretion via a liver/α cell axis. We hypothesized that α cells detect and respond to circulating amino acids’ levels via a unique amino acid transporter repertoire. We found that Slc7a2/SLC7A2 is the most highly expressed cationic amino acid transporter in α cells, with its expression being 3-fold greater in α than β cells in both mouse and human. Employing cell culture, zebrafish, and knockout mouse models, we found that the cationic amino acid arginine and SLC7A2 are required for α cell proliferation in response to interrupted glucagon signaling. Ex vivo and in vivo assessment of islet function in Slc7a2–/– mice showed decreased arginine-stimulated glucagon and insulin secretion. We found that arginine activation of mTOR signaling and induction of the glutamine transporter SLC38A5 was dependent on SLC7A2, showing that the role of both in α cell proliferation is dependent on arginine transport and SLC7A2. Finally, we identified single nucleotide polymorphisms in SLC7A2 associated with HbA1c. Together, these data indicate a central role for SLC7A2 in amino acid–stimulated α cell proliferation and islet hormone secretion.
Authors
Erick Spears, Jade E. Stanley, Matthew Shou, Linlin Yin, Xuan Li, Chunhua Dai, Amber Bradley, Katelyn Sellick, Greg Poffenberger, Katie C. Coate, Shristi Shrestha, Anna Marie R. Schornack, Taverlyn Shepard, Madushika Wimalarathne, Regina Jenkins, Kyle W. Sloop, Keith T. Wilson, Alan D. Attie, Mark P. Keller, Wenbiao Chen, Alvin C. Powers, E. Danielle Dean
Abstract
Obesity is associated with impaired wound healing, but the mechanisms linking excess adiposity to aberrant tissue repair remain unresolved. Heterotopic ossification (HO) is a severe example of pathologic tissue repair in which mesenchymal progenitor cells (MPCs) undergo aberrant osteochondral differentiation within soft tissue, leading to joint contractures and pain. Here, we show that accumulation of dietary omega-6 (ω-6) lipids in the injury site is a key mechanism linking obesity to HO. Specifically, in mice fed a high-fat diet (HFD), injured tissues were enriched in linoleic and arachidonic acids, providing substrate for myeloid cyclooxygenase-2 (COX-2)-dependent prostaglandin E2 (PGE2) production. PGE2 then drove a transcriptional program in mesenchymal progenitor cells that promoted osteochondral differentiation. An isocaloric, low linoleic acid HFD reduced HO despite comparable obesity, demonstrating that dietary lipid composition, rather than adiposity alone, drove pathological repair. Clinical data mirrored these findings, showing that obesity conferred increased HO risk, and COX-2 inhibition reduced HO exclusively in obese patients. Together, these findings identify injury site ω-6 lipid enrichment as the key signal linking the diet to MPC reprogramming, pointing to dietary lipid modulation as an actionable strategy to limit HO in obesity.
Authors
Stefanie L. Moye, Monisha Mittal, Tarun Srinivasan, Sneha Korlakunta, Chase A. Pagani, Ayelet Dar, Oromo Geshow, Dylan Feist, Lauren G. Zacharias, Zhao Li, Aaron W. James, Gerta Hoxhaj, Andrew M. Smith, Katherine A. Gallagher, Thomas P. Mathews, Robert J. Tower, Benjamin Levi
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)