Independent of mitochondrial respiratory function, dietary nitrate attenuates HFD-induced lipid accumulation and mitochondrial ROS emission within the liver

• Published in: American journal of physiology: endocrinology and metabolism Vol. 321; no. 2; pp. E217 - E228
• Main Authors: DesOrmeaux, Geneviève J, Petrick, Heather L, Brunetta, Henver S, Holloway, Graham P
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.08.2021
• Subjects: Accumulation; Acetyl-CoA carboxylase; Adenosine diphosphate; AMP-activated protein kinase; AMP-Activated Protein Kinases - metabolism; Animals; Antioxidants; Attenuation; Bioenergetics; Body weight gain; Diet; Diet, High-Fat; Dietary supplements; Electron transport; Emission; Fatty liver; Glucose; Glucose tolerance; High fat diet; Homeostasis; Insulin; Insulin - metabolism; Intolerance; Kinases; Lipid Metabolism; Lipids; Liver; Liver - metabolism; Male; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondria - metabolism; Nitrates; Nitrates - metabolism; Nitrotyrosine; Oxidative stress; Proteins; Pyruvic acid; Reactive oxygen species; Reactive Oxygen Species - metabolism; Respiratory function; Sensitivity; Signaling; Steatosis; Substrates; nitrate; liver; mitochondria; high-fat diet; reactive oxygen species
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00610.2020

The liver is particularly susceptible to the detrimental effects of a high-fat diet (HFD), rapidly developing lipid accumulation and impaired cellular homeostasis. Recently, dietary nitrate has been shown to attenuate HFD-induced whole body glucose intolerance and liver steatosis, however, the underlying mechanism(s) remain poorly defined. In the current study, we investigated the ability of dietary nitrate to minimize possible impairments in liver mitochondrial bioenergetics following 8 wk of HFD (60% fat) in male C57BL/6J mice. Consumption of a HFD caused whole body glucose intolerance ( < 0.0001), and within the liver, increased lipid accumulation ( < 0.0001), mitochondrial-specific reactive oxygen species emission ( = 0.007), and markers of oxidative stress. Remarkably, dietary nitrate attenuated almost all of these pathological responses. Despite the reduction in lipid accumulation and redox stress (reduced TBARS and nitrotyrosine), nitrate did not improve insulin signaling within the liver or whole body pyruvate tolerance ( = 0.313 HFD vs. HFD + nitrate). Moreover, the beneficial effects of nitrate were independent of changes in weight gain, 5' AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) signaling, mitochondrial content, mitochondrial respiratory capacity and ADP sensitivity or antioxidant protein content. Combined, these data suggest nitrate supplementation represents a potential therapeutic strategy to attenuate hepatic lipid accumulation and decrease mitochondrial ROS emission following HFD, processes linked to improvements in whole body glucose tolerance. However, the beneficial effects of nitrate within the liver do not appear to be a result of increased oxidative capacity or mitochondrial substrate sensitivity. The mechanism(s) for how dietary nitrate prevents high-fat diet (HFD)-induced glucose intolerance remain poorly defined. We show that dietary nitrate attenuates HFD-induced increases in lipid accumulation, mitochondrial-specific reactive oxygen species (ROS) emission, and markers of oxidative stress within the liver. The beneficial effects of nitrate were independent of changes 5' AMP-activated protein kinase signaling, mitochondrial content/respiratory capacity, or lipid-supported respiratory sensitivity. Combined, these data provide potential mechanisms underlying the therapeutic potential of dietary nitrate.