ArticleProceedings of the National Academy of Sciences of the United States of America2019
AMP-activated protein kinase activation and NADPH oxidase inhibition by inorganic nitrate and nitrite prevent liver steatosis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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41 citing papers in PubMed, 99 citations in OpenAlex.
- Effects of inorganic nitrate on ischaemia-reperfusion injury after coronary artery bypass surgery: a randomised controlled trial.British journal of anaesthesia · 2021Trial
- Advances in pharmacological interventions for hepatic fibrosis: from pathogenic mechanisms to novel therapeutic targets.Annals of medicine · 2026Review
- Oleanolic Acid Modulates the Gut-Liver Axis to Alleviate High-Fat Diet-Induced Hepatic Lipid Deposition in Nile Tilapia (Microorganisms · 2026Article
- The nitrate-Sialin axis: a new target for regulation of macrophage metabolic reprogramming and metabolic homeostasis.Medical review (2021) · 2026Article
- Dietary nitrate and resveratrol co-supplementation prevent HFD-mediated impairments in carotid blood flow and behavioral parameters in male mice.Physiological reports · 2026Article
- Long-Term Low-Dose of Nitrate Administration Improves Antioxidant Defence System in Insulin-Sensitive Tissues of Type 2 Diabetic Rats.Endocrinology, diabetes & metabolism · 2026Article
- A microphysiological model of human MASLD reveals paradoxical response to resmetirom.Communications biology · 2026Article
- Inhibition of hepatic gluconeogenesis in type 2 diabetes by metformin: complementary role of nitric oxide.Medical gas research · 2025Review
- Sodium nitrate protects against metabolic syndrome by sialin-mediated macrophage rebalance.Signal transduction and targeted therapy · 2025Article
- Optimal Vegetable Intake for Metabolic-Dysfunction-Associated Steatotic Liver Disease (MASLD) Prevention: Insights from a South Italian Cohort.Nutrients · 2025Article
- Prevention of Metabolic Impairment by Dietary Nitrate in Overweight Male Mice Improves Stroke Outcome.Nutrients · 2025Article
- Dietary nitrate preserves mitochondrial bioenergetics and mitochondrial protein synthesis rates during short-term immobilization in mice.The Journal of physiology · 2025Article
- Aging-Associated Liver Sinusoidal Endothelial Cells Dysfunction Aggravates the Progression of Metabolic Dysfunction-Associated Steatotic Liver Disease.Aging cell · 2025Article
- Associations between intake of different types of vegetables and metabolic dysfunction-associated fatty liver disease: a population-based study.BMC public health · 2025Article
- Role of oral and gut microbiomes in enterosalivary nitrate metabolism and their effects on systemic disease.Frontiers in cellular and infection microbiology · 2025Review
- The Nitrate-Nitrite-Nitric Oxide Pathway: Potential Role in Mitigating Oxidative Stress in Hypertensive Disorders of Pregnancy.Nutrients · 2024Review
- Antibacterial mouthwash alters gut microbiome, reducing nutrient absorption and fat accumulation in Western diet-fed mice.Scientific reports · 2024Article
- Lipotoxicity as a therapeutic target in obesity and diabetic cardiomyopathy.Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques · 2024Review
- From nitrate to NO: potential effects of nitrate-reducing bacteria on systemic health and disease.European journal of medical research · 2023Review
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Authors and funding
16 authors at 2 institutions in 2 countries.
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Abstract
Advanced age and unhealthy dietary habits contribute to the increasing incidence of obesity and type 2 diabetes. These metabolic disorders, which are often accompanied by oxidative stress and compromised nitric oxide (NO) signaling, increase the risk of adverse cardiovascular complications and development of fatty liver disease. Here, we investigated the therapeutic effects of dietary nitrate, which is found in high levels in green leafy vegetables, on liver steatosis associated with metabolic syndrome. Dietary nitrate fuels a nitrate-nitrite-NO signaling pathway, which prevented many features of metabolic syndrome and liver steatosis that developed in mice fed a high-fat diet, with or without combination with an inhibitor of NOS (l-NAME). These favorable effects of nitrate were absent in germ-free mice, demonstrating the central importance of host microbiota in bioactivation of nitrate. In a human liver cell line (HepG2) and in a validated hepatic 3D model with primary human hepatocyte spheroids, nitrite treatment reduced the degree of metabolically induced steatosis (i.e., high glucose, insulin, and free fatty acids), as well as drug-induced steatosis (i.e., amiodarone). Mechanistically, the salutary metabolic effects of nitrate and nitrite can be ascribed to nitrite-derived formation of NO species and activation of soluble guanylyl cyclase, where xanthine oxidoreductase is proposed to mediate the reduction of nitrite. Boosting this nitrate-nitrite-NO pathway results in attenuation of NADPH oxidase-derived oxidative stress and stimulation of AMP-activated protein kinase and downstream signaling pathways regulating lipogenesis, fatty acid oxidation, and glucose homeostasis. These findings may have implications for novel nutrition-based preventive and therapeutic strategies against liver steatosis associated with metabolic dysfunction.
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