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AMP-activated protein kinase activation and NADPH oxidase inhibition by inorganic nitrate and nitrite prevent liver steatosis
- Source :
- Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences of the United States of America
- Publication Year :
- 2018
- Publisher :
- Proceedings of the National Academy of Sciences, 2018.
-
Abstract
- Significance Liver steatosis, or fatty liver, is the most common liver disease in the world, affecting up to 25% of all Americans. There is currently no approved drug available for this condition, which may progress to serious disease, including steatohepatitis, fibrosis, and cirrhosis. Here, we show in rodent and human models of metabolic syndrome that steatosis can be prevented by a simple dietary approach. Inorganic nitrate, present in green leafy vegetables, is converted in vivo to nitric oxide (NO) in a process involving symbiotic host bacteria. NO then induces key metabolic regulatory pathways to ultimately reduce oxidative stress and improve cardiometabolic functions. Clinical trials would be helpful to tell if dietary nitrate is useful in treatment and prevention of fatty liver disease.<br />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.
- Subjects :
- Male
0301 basic medicine
medicine.medical_specialty
Medical Sciences
AMP-Activated Protein Kinases
030204 cardiovascular system & hematology
Nitric Oxide
medicine.disease_cause
Nitric oxide
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
AMP-activated protein kinase
nitrate
Internal medicine
steatosis
microbiota
medicine
Animals
Humans
Glucose homeostasis
nitrite
Nitrites
2. Zero hunger
Nitrates
Multidisciplinary
NADPH oxidase
biology
Fatty liver
NADPH Oxidases
Hep G2 Cells
Biological Sciences
medicine.disease
3. Good health
Enzyme Activation
Fatty Liver
Mice, Inbred C57BL
030104 developmental biology
Endocrinology
Liver
PNAS Plus
chemistry
Lipogenesis
Hepatocytes
biology.protein
Steatosis
Oxidative stress
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 116
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....31918cbc3e5d864219ec4bb6b718e045