Metabolism
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease driven by aberrant fibroblast-to-myofibroblast differentiation, which requires metabolic reprogramming. Here, we identify alanine as an essential metabolite for myofibroblast differentiation. Transforming growth factor–β1 (TGF-β) increases intracellular alanine levels through enhanced synthesis and import in both normal and IPF lung fibroblasts. Alanine synthesis is primarily mediated by glutamate-pyruvate transaminase 2 (GPT2), whose expression is regulated by the glutamine–glutamate–α-ketoglutarate axis. Inhibition of GPT2 depletes alanine and suppresses TGF-β-induced α-SMA and COL1A1 expression, which are rescued by exogenous alanine. We also identify solute carrier family 38 member 2 (SLC38A2) as a transporter for both alanine and glutamine, upregulated by TGF-β or alanine deprivation. SLC38A2 and GPT2 form a coordinated regulatory axis sustaining intracellular alanine levels to support myofibroblast differentiation. Mechanistically, alanine deficiency impairs glycolytic flux and depletes tricarboxylic acid cycle intermediates, while alanine supplementation provides carbon and nitrogen for intracellular glutamate and proline biosynthesis, particularly under glutamine deprivation. Combined inhibition of alanine synthesis and uptake suppresses fibrogenic responses in fibroblasts and human precision-cut lung slices, highlighting dual metabolic targeting as a potential therapeutic strategy for fibrotic lung disease.
Authors
Fei Li, Niv Vigder, David R. Ziehr, Mari Kamiya, Hung N. Nguyen, Diana E. Ferreyra Faustino, Aseel H. Khalil, Hilaire C. Lam, Matthew L. Steinhauser, Edy Y. Kim, William M. Oldham
Abstract
High dietary salt intake elevates blood pressure and drives multi-organ damage. However, the molecular programs underlying progressive organ injury remain poorly defined. Here, we present a longitudinal multi-organ transcriptomic atlas of salt-induced hypertensive injury. We profiled kidney cortex, kidney medulla, heart, and liver across four stages spanning early hypertension to advanced pathology in Dahl salt-sensitive rats. We identified dynamic and tissue-specific molecular trajectories, including a shared early proliferative response that converges on proinflammatory and fibrotic remodeling. Notably, we uncovered compartment-specific renal responses, showing that the cortex and medulla, despite their proximity, follow distinct molecular trajectories during disease progression. We further identified 79 stage- and tissue-specific transcription factors that drive gene expression dynamics in salt-induced hypertensive injury. Integration with human genome-wide association studies revealed conserved pathways in endocrine signaling, ion transport, lipid metabolism, and detoxification, establishing cross-species relevance and highlighting mechanistic targets of clinical importance. Compound–transcriptome analysis revealed stage- and organ-specific therapeutic opportunities, prioritizing kinase and epigenetic modulators as candidates to rebalance maladaptive gene programs. Overall, this study provides a resource for understanding molecular mechanisms from early salt-induced hypertension to tissue-specific injury and underscores the need for precision interventions.
Authors
Ratnakar Tiwari, Olha Kravtsova, Lashodya V. Dissanayake, Melissa Lowe, Biyang Xu, Vladislav Levchenko, Steven Didik, Ruslan Bohovyk, Daria V. Ilatovskaya, Oleg Palygin, Alexander Staruschenko
Abstract
Lipotoxicity associated with metabolic dysfunction-associated steatotic liver disease (MASLD) causes dysregulated fatty acid (FA) and glucose metabolism, inducing cellular energy imbalance, oxidative stress (OS), and hepatocellular injury. Interleukin (IL)-10 is altered in MASLD, including increased IL-10 transcripts in peripheral immune cells; however, its role in hepatic responses to lipotoxic stress remains unclear. We evaluated whether IL-10 treatment attenuates lipotoxic injury and MASLD-related phenotypes in vivo and in vitro to reveal MASLD treatment strategies. As MASLD models, in vivo high-fat diet mice and in vitro normal human hepatocytes under palmitic acid exposure, with confirmatory experiments in HepG2 cells, were used and treated with IL-10. We assessed FA and glucose metabolism, OS, and apoptosis with histological changes and mechanisms related to hepatocellular viability/metabolic activity and stress-responsive survival signaling in vitro. IL-10 modulated FA synthesis and β-oxidation, reducing lipid accumulation, and altered glucose metabolic pathways, consistent with improved glucose handling under lipotoxic stress. Furthermore, IL-10 reduced OS and cell death markers while enhancing antioxidant responses, consistent with hepatocellular protection. These data suggest that IL-10 attenuates lipotoxic injury by modulating hepatic response pathways, thereby improving MASLD-related phenotypes, and supports the potential of IL-10 as a therapeutic target for MASLD.
Authors
Akira Kado, Kazuya Okushin, Takeya Tsutsumi, Toshiyuki Kishida, Kazuhiko Ikeuchi, Hiroshi Yotsuyanagi, Kyoji Moriya, Kazuhiko Koike, Mitsuhiro Fujishiro
Abstract
Increased consumption of ultra-processed foods (UPFs) is a risk factor for metabolic disorders-associated heart failure (HF). Here, we demonstrate that UPF-induced calpain-1 aggravated oxidative stress, thereby increasing high mobility group box 1 (HMGB1)-mediated myocardial inflammation, which contributes to cardiac dysfunction. After illustrating the dysregulated inflammatory pathways in human and murine hearts upon metabolic stress, we revealed an increase in calpain-1 alongside profound oxidative stress and inflammation in the failing myocardium. Mechanistically, in neonatal rat cardiomyocytes (NRCMs) and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), HMGB1 was upregulated by calpain-1 and reactive oxygen species (ROS) upon stress of saturated and trans fatty acids (FA). Consequently, HMGB1 promoted a pro-inflammatory response in macrophages. On the contrary, inhibition of calpain or ROS efficiently repressed HMGB1 in cardiomyocytes. Therapeutically, either recombinant adeno-associated virus 9 (AAV9) delivered inhibitor of calpain-1 or its pharmacological inhibitor attenuated ROS and HMGB1-induced inflammation in the myocardium and mitigated HF in both male and female mice fed with an ultra-processed diet (UPD). Collectively, we have demonstrated the effects of suppressing calpain-1 and oxidative stress on alleviating myocardial inflammation via blockage of HMGB1 and cardiac dysfunction. The results provide a promising therapeutic strategy for preventing or treating HF in metabolic disorders.
Authors
Claire Ross, Sanskruti Ravindra Gare, Nasser H. Alatawi, Oveena Fonseka, Xinyi Chen, Jiayan Zhang, Yihua Han, Andrea Ruiz-Velasco, Riham R.E. Abouleisa, Yingjuan Liu, Xiangjun Zhao, Han Xiao, Bernard Keavney, Gareth J. Howell, Tao Wang, Tamer M.A. Mohamed, Elizabeth J. Cartwright, Wei Liu
Abstract
Hypothalamic melanocortin 4 receptors (MC4Rs) play a central role in regulating food intake and energy homeostasis. In fact, inactivating mutations in the MC4R gene are the most common form of monogenic obesity. Agonist activation of MC4Rs reduces food intake by modulating hypothalamic signaling circuits. Thus, a detailed understanding of the signaling pathways that regulate MC4R activity is of considerable translational relevance. Ligand-activated MC4Rs interact not only with heterotrimeric G proteins but can also recruit beta-arrestin-2 (barr2) to the receptor. The potential functional role of barr2 in regulating the anorectic effects of MC4R signaling remains unexplored. In the present study, we used mutant mouse models to demonstrate that MC4R-mediated activation of barr2/ERK signaling in MC4R neurons of the paraventricular nucleus leads to reduced food intake. We also found that the appetite-suppressing effect of setmelanotide, an MC4R agonist approved by the FDA for the treatment of certain types of obesity, requires the presence of barr2 in MC4R-containing neurons. These data suggest that MC4R agonists able to promote MC4R/barr2 interactions with high efficacy may become useful as appetite-suppressing drugs.
Authors
Misbah Rashid, Lei Wang, Zhenzhong Cui, Oksana Gavrilova, Huiyan Lu, Kozo Kaibuchi, Sarah Zeitlmayr, Thomas Gudermann, Andreas Breit, Jürgen Wess
Abstract
Interscapular brown adipose tissue (iBAT), one of the most vascularized tissues in the body, exemplifies the intricate crosstalk between the vascular system and adipocytes. BAT is known to secrete abundant exosomes into circulation, while exosomes are known to play a key role in vascular remodeling and cell migration. However, whether BAT-derived exosomes (BATexos) modulate peripheral vasculature remains unclear. Here, we report that BATexos promoted peripheral angiogenesis and vascular repair. Among their cargo, miR-378a-3p was highly enriched and identified as a key mediator of endothelial angiogenic function. The overexpression of miR-378a-3p in endothelial cells substantially promoted cell migration and tube formation. Conversely, inhibition of exosome secretion from BAT impaired vascular repair and delayed wound healing. Mechanistically, miR-378a-3p directly targeted the phosphatase and tensin homolog (Pten), thereby activating the PI3K-AKT signaling pathway. Liposomes encapsulating miR-378 mimics promoted angiogenesis and accelerated wound healing in a diabetic mouse model. Collectively, this study uncovers BAT-derived miR-378a-3p as a key regulator of vessel regeneration and tissue repair following injury, offering new therapeutic potential for treating vascular complications in metabolic disease.
Authors
Hongyan Deng, Yuyu Xie, Jiadai Liu, Jing Ge, Qianqian Kang, Rui He, Zhihan Wang, Xuemin Peng, Zengzhe Zhu, Wenshe Wang, Yulian Liu, Ronghui Gao, Ruping Pan, Min Yang, Yong Chen
Abstract
Subendothelial retention of cholesterol-rich apolipoprotein-B-containing lipoproteins drives atherosclerotic arterial disease. In peripheral interstitial fluid from patients with type 2 diabetes (T2D), levels of such particles have been shown to be paradoxically reduced relative to those in serum, presumably reflecting their increased retention within the arterial wall. To identify possible mechanisms involved in lipoprotein retention in T2D, we obtained serum and skin blister fluid from such patients and matched controls, together with skin biopsies in a subset of individuals. In T2D, smaller LDL and VLDL remnant particles were more prominent in serum, but not in interstitial fluid, reflecting their enhanced vascular entrapment. The interstitial-fluid-to-serum ratio of apolipoprotein-B was 58% lower in T2D than in controls (0.14 vs 0.33), concomitant with increased susceptibility for LDL binding to proteoglycans. The most marked differences were seen in patients with clinically evident cardiovascular disease. The degree of transvascular retention was positively related to the propensity of isolated serum LDL to bind aortic proteoglycans, both in T2D and in controls. Skin unesterified cholesterol levels were higher in T2D patients relative to healthy controls. With aging, both proteoglycan binding and apparent vascular retention of LDL increased in controls, but not in T2D, indicating that these mechanisms may also be relevant for atherogenesis in non-diabetic individuals.
Authors
Pär Björklund, Jennifer Härdfeldt, Lauri Äikäs, Sara Straniero, Minna Holopainen, Katariina Öörni, Mats J. Rudling, Bo Angelin
Abstract
Huntington’s disease (HD) is a fatal neurodegenerative disease caused by an expanded polyglutamine (CAG) repeat in the N-terminal of the Huntingtin protein (HTT). Microglial activation and elevated pro-inflammatory cytokines are observed in HD brains, but the mechanisms regulating neuroinflammation and microglial activation are poorly understood. Metformin-mediated neuroprotection has been demonstrated in experimental models of neurodegeneration, including HD. We found that metformin inhibits mitochondrial DNA (mtDNA) release and subsequent neuroinflammation in the cortex and striatum of a mouse model of HD. Moreover, elevated pro-inflammatory cytokines and microglial activation are inhibited by metformin in HD transgenic mice brain. Metformin reduced pathological microglial clusters and shifted towards a quiescent, homeostatic phenotype. Metformin improved aberrant immunometabolism in HD mouse brain and primary microglia. Mechanistically found that metformin regulates mitochondrial fission, reprograms deregulated metabolism in HD microglia, and controls microglial activation and inflammation in HD transgenic mice.
Authors
Abhishek Jauhari, Adam C. Monek, Olena S. Abakumova, Tanisha Singh, Sukhman Singh, Xiaomin Wang, Carley S. Clise, Diane L. Carlisle, Robert M. Friedlander
Abstract
Authors
Anna J. Son, Emmanuel Rapp, Alex Wiezorek, Max G. Leung, Ronadip R. Banerjee, Thomas H. Leung
Abstract
A large inter-individual variability in weight loss outcomes following bariatric surgery is reported. To ensure optimal patient management, it is crucial to accurately identify those most likely to benefit from the intervention. Since genetic variants largely contribute to surgery response, polygenic scores (PGS) derived from genome-wide association studies (GWAS) could constitute valuable tools for clinical decision making. We developed and evaluated PGS to predict the weight loss response in 540 patients with body mass index (BMI) ≥35kg/m2 who underwent biliopancreatic diversion with duodenal switch. Summary statistics derived from BMI-derived GWAS, together with summary statistics from previously published GWAS of BMI and adiposity features, were used to construct, evaluate, and benchmark weight-loss PGS. The full-adjusted BMI PGS model built in the entire cohort explained 39.6% of the mean-over-time excessive body weight loss (%EBWL), while the BMI-PGS built in the training dataset explained 38.9%. All benchmarked PGS based on BMI showed a significant relationship with mean-over-time %EBWL. These findings highlight the potential of BMI PGS in predicting weight loss after bariatric surgery and support their use as promising tools to improve the effectiveness of future anti-obesity treatments. Funding: Canadian Institutes of Health Research (PJT-168876).
Authors
Bastien Vallée Marcotte, Juan de Toro-Martín, André Tchernof, Louis Pérusse, Simon Marceau, Marie-Claude Vohl
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