Associations between fatty acid oxidation, hepatic mitochondrial function, and plasma acylcarnitine levels in mice

Abstract

BackgroundThe 4-thia fatty acid tetradecylthiopropionic acid (TTP) is known to inhibit mitochondrial β-oxidation, and can be used as chemically induced hepatic steatosis-model in rodents, while 3-thia fatty acid tetradecylthioacetic acid (TTA) stimulates fatty acid oxidation through activation of peroxisome proliferator activated receptor alpha (PPARα). We wished to determine how these two compounds affected in vivo respiration and mitochondrial efficiency, with an additional goal to elucidate whether mitochondrial function is reflected in plasma acylcarnitine levels.MethodsC57BL/6 mice were divided in 4 groups of 10 mice and fed a control low-fat diet, low-fat diets with 0.4% (w/w) TTP, 0.4% TTA or a combination of these two fatty acids for three weeks (n = 10). At sacrifice, β-oxidation and oxidative phosphorylation (OXPHOS) capacity was analysed in fresh liver samples. Hepatic mitochondria were studied using transmission electron microscopy. Lipid classes were measured in plasma, heart and liver, acylcarnitines were measured in plasma, and gene expression was measured in liver.ResultsThe TTP diet resulted in hepatic lipid accumulation, plasma L-carnitine and acetylcarnitine depletion and elevated palmitoylcarnitine and non-esterified fatty acid levels. No significant lipid accumulation was observed in heart. The TTA supplement resulted in enhanced hepatic β-oxidation, accompanied by an increased level of acetylcarnitine and palmitoylcarnitine in plasma. Analysis of mitochondrial respiration showed that TTP reduced oxidative phosphorylation, while TTA increased the maximum respiratory capacity of the electron transport system. Combined treatment with TTP and TTA resulted in a profound stimulation of genes involved in the PPAR-response and L-carnitine metabolism, and partly prevented triacylglycerol accumulation in the liver concomitant with increased peroxisomal β-oxidation and depletion of plasma acetylcarnitines. Despite an increased number of mitochondria in the liver of TTA + TTP fed mice, the OXPHOS capacity was significantly reduced.ConclusionThis study indicates that fatty acid β-oxidation directly affects mitochondrial respiratory capacity in liver. As plasma acylcarnitines reflected the reduced mitochondrial β-oxidation in TTP-fed mice, they could be useful tools to monitor mitochondrial function. As mitochondrial dysfunction is a major determinant of metabolic disease, this supports their use as plasma markers of cardiovascular risk in humans. Results however indicate that high PPAR activation obscures the interpretation of plasma acylcarnitine levels.Electronic supplementary materialThe online version of this article (10.1186/s12986-018-0241-7) contains supplementary material, which is available to authorized users.

Vitamin C Administration Attenuated Artemether Induced Hepatic Injury in Rats

“…Spaces of Disse were seen around hepatocytes expanded and filled with long fragmented microvilli which cause the distinct clarification of the cell's borders under the light microscopy examination. It also showed cytoplasmic vacuoles and sinusoids were filled with hypertrophy of Kupffer cells which is in accordance with Bjørndal et al (2018) who reported that the neutral fat accumulates in the liver frequently, is due to inhibition of aerobic oxidation. Furthermore, artemether has been shown to induce transient and moderate elevations in liver transaminases (Nwanjo et al, 2007).…”

Macrophage Function in the Pathogenesis of Non-alcoholic Fatty Liver Disease: The Mac Attack

“…Mitochondrial-beta oxidation breaks down short (<C 8 ), medium (C 8 -C 14 ) and long chain FA (C 14 -C 20 ) (85). Long chain FA, which are a major component of the standard diet, are shuttled into the mitochondria via carnitine shuttles (carnitine palmitoyltransferase I) by linking with coenzyme A (acyl-CoA) (85,112). Once acylcarnitine exchanges the carnitine molecule with CoA via exchange with carnitine palmitoyltransferase II the acyl-CoA proceeds into the betaoxidation cycle.…”

Adipose tissues of MPC1± mice display altered lipid metabolism-related enzyme expression levels

“…ACAT2 is the major cholesterol-esterifying enzyme that plays a critical role in preventing murine atherosclerosis and hypertriglyceridemia ( Alger et al, 2010 ). Ehhadh is part of the classical peroxisomal fatty acid β -oxidation pathway, which is highly inducible via peroxisome proliferator-activated receptor α (PPAR α ) activation ( Bjorndal et al, 2018 ). Strong associations between fads1 and blood fatty acid levels have been reported, particularly that between fads1 and PUFAs and long-chain PUFAs ( Glaser, Heinrich & Koletzko, 2010 ).…”