Saranya Reghupaty

All Publications

• Genetic depletion of adipose-derived Isthmin-1 causes hepatic steatosis. Molecular metabolism Reghupaty, S. C., Coassolo, L., Zhao, M., Narasimhan, R. L., Patel, A., Lone, J., Bielczyk-Maczynska, E., Danneskiold-Samsoee, N. B., Brown, T., Jiang, Z., Li, V. L., Svensson, K. J. 2025: 102172

  Abstract

  Adipose tissue plays a critical role in obesity, as its dysfunction can impair lipid homeostasis and result in lipid overflow and ectopic lipid deposition in the liver. We previously demonstrated that Isthmin-1 (Ism1) regulates glucose uptake into the adipose tissue and suppresses hepatic steatosis, but the role of adipose-derived Ism1 is unknown. Here, we investigate the role of adipose-derived Ism1 in metabolic health and its impact on hepatic steatosis and lipid metabolism.In this study, we employed both a genetic knockout approach, selectively deleting Ism1 in adipose tissue of mice (AdipoQ-Ism1-KO), and a pharmacological approach by administering recombinant Ism1 protein to mice. These mice were subjected to a high fat-high fructose diet to simulate conditions that promote Metabolic-dysfunction Associated Steatotic Liver Disease (MASLD).AdipoQ-Ism1-KO are of normal weight, but prone to severe hepatic steatosis in response to high fat-high fructose feeding. Lipidomic profiling through untargeted analyses in both gain-of-function and loss-of-function models was used to assess changes in hepatic lipid homeostasis. These results provide in vivo genetic support for the role of Ism1 as a regulator of the adipose-hepatic axis.Collectively, these data demonstrate that loss of adipose-derived Ism1 disrupts lipid homeostasis and accelerates the development of hepatic steatosis. This study provides a genetic basis for Ism1's involvement in metabolic regulation, suggesting a potential therapeutic target for treating metabolic disorders.

  View details for DOI 10.1016/j.molmet.2025.102172

  View details for PubMedID 40436204

• TATA-box binding protein-associated factor 2 (TAF2) in hepatocyte survival and tumorigenesis HEPATOLOGY Reghupaty, S., Raha, S., Mendoza, R., Manna, D., Gawi Ermi, A., Davis, E., Aqeel, Y., Subler, M. A., Koblinski, J., Idowu, M., Mukhopadhyay, N., Lai, Z., Fisher, P. B., Windle, J. J., Dozmorov, M. G., Sarkar, D. 2025

  Abstract

  Chromosome 8q amplification is a frequent event in cancers, including HCC. TATA-box binding protein associated factor 2 (TAF2), a component of transcription factor IID (TFIID) residing in 8q24.12, is amplified in HCC. As yet, a potential oncogenic function of TAF2 in HCC has not been documented.We identified TAF2 mRNA and protein overexpression in human HCC cells and tissue samples, compared to their normal counterparts. A significant negative correlation between TAF2 levels and the overall survival of HCC patients was observed. The role of TAF2 in HCC regulation was examined using a hepatocyte-specific conditional knockout mouse (Taf2 ΔHEP ), TAF2 knockdown and overexpression in human HCC cells, and TAF2 overexpression in mouse liver by hydrodynamic approach. As a core component of basal transcription machinery, TAF2 is required for hepatocyte survival. As such, in Taf2 ΔHEP mice, there was hepatocyte death and compensatory proliferation, contributing to an inflammatory/fibrotic milieu favoring HCC. Accordingly, N-nitrosodiethylamine (DEN)/high-fat high-sugar diet-induced HCC was robustly augmented in Taf2 ΔHEP mice compared to their wild-type littermates. TAF2 overexpression in mouse liver did not lead to tumor development, but significantly augmented HCC that was induced by overexpression of the driver oncogene MYC. TAF2 augmented cancer hallmarks in human HCC cells by binding to the promoters of tumor-promoting genes and non-coding RNAs and regulating their transcription.TAF2 plays a unique and central role in hepatocyte survival and tumorigenesis.

  View details for DOI 10.1097/HEP.0000000000001406

  View details for Web of Science ID 001524305500001

  View details for PubMedID 40392063

• Progress in Understanding the Regulation of Glucose and Fructose Metabolism. Annual review of nutrition Zhao, M., Lone, J., Reghupaty, S., Linde-Garelli, K. Y., Svensson, K. J. 2025

  Abstract

  Hexoses, including glucose, fructose, and galactose, are six-carbon monosaccharides that play fundamental roles in mammalian metabolism, with glucose serving as the primary energy source and fructose and galactose metabolized through pathways converging with glucose metabolism. While glucose metabolism has been extensively studied over the past hundred years, the mechanisms of fructose metabolism and uptake, the transporters involved, and its roles in physiology and disease are far less explored. Recent data also suggest that excessive fructose intake can have detrimental effects on metabolic organs, including the liver. Emerging studies have uncovered novel regulatory mechanisms in glucose and fructose metabolism, including the role of posttranslational modifications of transporters and enzymes, and the discovery of regulators of transporters. Here, we highlight new findings on the regulation of glucose and fructose transporters and integrate recent molecular and clinical insights into how glucose and fructose contribute to metabolic diseases.

  View details for DOI 10.1146/annurev-nutr-111824-012939

  View details for PubMedID 40249960

• PTER is a N-acetyltaurine hydrolase that regulates feeding and obesity. Nature Wei, W., Lyu, X., Markhard, A. L., Fu, S., Mardjuki, R. E., Cavanagh, P. E., Zeng, X., Rajniak, J., Lu, N., Xiao, S., Zhao, M., Moya-Garzon, M. D., Truong, S. D., Chou, J. C., Wat, L. W., Chidambaranathan-Reghupaty, S., Coassolo, L., Xu, D., Shen, F., Huang, W., Ramirez, C. B., Jang, C., Li, L., Svensson, K. J., Fischbach, M. A., Long, J. Z. 2024

  Abstract

  Taurine is a conditionally essential micronutrient and one of the most abundant amino acids in humans1-3. In endogenous taurine metabolism, dedicated enzymes are involved in the biosynthesis of taurine from cysteine and in the downstream metabolism of secondary taurine metabolites4,5. One taurine metabolite is N-acetyltaurine6. Levels of N-acetyltaurine are dynamically regulated by stimuli that alter taurine or acetate flux, including endurance exercise7, dietary taurine supplementation8 and alcohol consumption6,9. So far, the identities of the enzymes involved in N-acetyltaurine metabolism, and the potential functions of N-acetyltaurine itself, have remained unknown. Here we show that the body mass index associated orphan enzyme phosphotriesterase-related (PTER)10 is a physiological N-acetyltaurine hydrolase. In vitro, PTER catalyses the hydrolysis of N-acetyltaurine to taurine and acetate. In mice, PTER is expressed in the kidney, liver and brainstem. Genetic ablation of Pter in mice results in complete loss of tissue N-acetyltaurine hydrolysis activity and a systemic increase in N-acetyltaurine levels. After stimuli that increase taurine levels, Pter knockout mice exhibit reduced food intake, resistance to diet-induced obesity and improved glucose homeostasis. Administration of N-acetyltaurine to obese wild-type mice also reduces food intake and body weight in a GFRAL-dependent manner. These data place PTER into a central enzymatic node of secondary taurine metabolism and uncover a role for PTER and N-acetyltaurine in body weight control and energy balance.

  View details for DOI 10.1038/s41586-024-07801-6

  View details for PubMedID 39112712

  View details for PubMedCentralID 3501277

• Hallmarks of the metabolic secretome. Trends in endocrinology and metabolism: TEM Reghupaty, S. C., Dall, N. R., Svensson, K. J. 2023

  Abstract

  The identification of novel secreted factors is advancing at an unprecedented pace. However, there is a critical need to consolidate and integrate this knowledge to provide a framework of their diverse mechanisms, functional significance, and inter-relationships. Complicating this effort are challenges related to nonstandardized methods, discrepancies in sample handling, and inconsistencies in the annotation of unknown molecules. This Review aims to synthesize the rapidly expanding field of the metabolic secretome, encompassing the five major types of secreted factors: proteins, peptides, metabolites, lipids, and extracellular vesicles. By systematically defining the functions and detection of the components within the metabolic secretome, this Review provides a primer into the advances of the field, and how integration of the techniques discussed can provide a deeper understanding of the mechanisms underlying metabolic homeostasis and its disorders.

  View details for DOI 10.1016/j.tem.2023.09.006

  View details for PubMedID 37845120

• Melanoma differentiation associated gene-9/syndecan binding protein promotes hepatocellular carcinoma HEPATOLOGY Manna, D., Reghupaty, S., Camarena, M., Mendoza, R. G., Subler, M. A., Koblinski, J. E., Martin, R., Dozmorov, M. G., Mukhopadhyay, N. D., Liu, J., Qu, X., Das, S. K., Lai, Z., Windle, J. J., Fisher, P. B., Sarkar, D. 2023; 78 (6): 1727-1741

  Abstract

  The oncogene Melanoma differentiation associated gene-9/syndecan binding protein (MDA-9/SDCBP) is overexpressed in many cancers, promoting aggressive, metastatic disease. However, the role of MDA-9 in regulating hepatocellular carcinoma (HCC) has not been well studied.To unravel the function of MDA-9 in HCC, we generated and characterized a transgenic mouse with hepatocyte-specific overexpression of MDA-9 (Alb/MDA-9). Compared with wild-type (WT) littermates, Alb/MDA-9 mice demonstrated significantly higher incidence of N-nitrosodiethylamine/phenobarbital-induced HCC, with marked activation and infiltration of macrophages. RNA sequencing (RNA-seq) in naive WT and Alb/MDA-9 hepatocytes identified activation of signaling pathways associated with invasion, angiogenesis, and inflammation, especially NF-κB and integrin-linked kinase signaling pathways. In nonparenchymal cells purified from naive livers, single-cell RNA-seq showed activation of Kupffer cells and macrophages in Alb/MDA-9 mice versus WT mice. A robust increase in the expression of Secreted phosphoprotein 1 (Spp1/osteopontin) was observed upon overexpression of MDA-9. Inhibition of NF-κB pathway blocked MDA-9-induced Spp1 induction, and knock down of Spp1 resulted in inhibition of MDA-9-induced macrophage migration, as well as angiogenesis.Alb/MDA-9 is a mouse model with MDA-9 overexpression in any tissue type. Our findings unravel an HCC-promoting role of MDA-9 mediated by NF-κB and Spp1 and support the rationale of using MDA-9 inhibitors as a potential treatment for aggressive HCC.

  View details for DOI 10.1002/hep.32797

  View details for Web of Science ID 000866106300001

  View details for PubMedID 36120720