Butyric acid can improve mitochondrial function, alleviate oxidative stress and ameliorate fatty liver

Fatty liver of livestock and poultry

Fatty liver disease are widelly found in multiple animals, such as pigs, chickens, cattle, sheep, and fish etc., has become a vital factor to affect animal health and meat quality, and many factors such as genetics, nutrition, management, drugs and toxins etc. are possibly the reasons lead to a fatty liver. The formation of fatty liver is related to a disorder of the fat metabolism that the fatty synthesis of liver cells are increased and the oxidation are decreased. The oxidative stress, disruption of NO signaling pathway and mitochondrial dysfunction are considered to be the key mechanisms to accelerate steatosis and trigger the process of fatty liver and fibrosis’. And at the same, there also are some complicated interactions between mitochondrial damage and oxidative stress.

Mitochondrial dysfunction

Mitochondria are known as the "Cell power plant". In addition to supplying energy to cellular, mitochondria are also involved in a range of processes, such  as  signaling, cellular differentiation and growth, and cell death. As one of the most important organelles of hepatocytes, mitochondria are the main site of fatty acid β-oxidation, tricarboxylic acid cycle, adenine nucleoside triphosphate (ATP) synthesis and ROS formation. Ischemia, hypoxia, drugs, and toxins etc. are the possibilties would lead to a mitochondrial dysfunction, which would manifeste as changes of morphological structure, ATP reduction, free oxygen’s excessive production, cell apoptosis, calcium disorder, and mtDNA damage, etc.

Liver mitochondria dysfunction causes some changes on fat oxidation. Mitochondrial fatty acid’s β oxidation is the rate-limiting step of fat metabolism, the mitochondrial dysfunction causes the oxidative phosphorylation of free fatty acids consumed by hepatocytes, the decreasing of β-oxidation, the increasing of the synthesization and ingestion of triglycerides, and that’s how the fatty liver is caused.

The dysfunction of liver mitochondria will cause a production of ROS and change of oxidative stress. At the cellular level, weaning, disease and fatty liver problems are all the oxidative stress of cells and mitochondria is the target of oxidative stress. A large number of studies have reported that in the process of fatty liver formation, with the massive production of ROS, the accumulation of mitochondrial oxidative damage products such as malondialdehyde (MDA) starts to rise up, and the levels of the main antioxidant proteins GSH, SOD2 and GPX in the mitochondria are significantly reduced. The antioxidant defense system is damaged and the oxidative stress occurred, further reducing the mitochondria oxidative respiratory function. 

Butyric acid improves mitochondrial function

As an important short chain fatty acid (SCFA), butyric acid has the functions of anti-inflammatory, anti-cancer, anti-oxidation and immune regulation. Butyric acid can not only be directly used as the energy matrix, but also act as a signal molecule to regulate gene and protein expression. For example, by inhibiting histone deacetylase (HDAC) or activating G-protein-coupled receptors 41 and 43, butyric acid regulates mitochondrial gene expression and affects the body metabolic activity.

Butyric acid can affect the occurrence and development of nonalcoholic fatty liver by reducing inflammatory response, inhibiting insulin resistance and weakening mitochondrial oxidative stress. He Jintian et al. found out that tributyrin nutrition intervention in intrauterine growth retardation (IUGR) piglets will improve the liver antioxidant capacity, protect mitochondria from damage, and significantly improve the liver SDH, MDH and Mn-SOD activities of IUGR piglets, so as to improve the working performance of liver mitochondrial function.

The obesity in mice and nonalcoholic fatty liver in rats would be possibly alleviated by butyric acid through enhancing the function performance of liver mitochondria. Studies of Hatzis et al. showed that a supplement of sodium butyrate could enhance the synthesis of melatonin in the intestine, and by which have reduced the endotoxin-induced active oxygen production and liver oxidative stress, thereby to protect liver diseases induced by high-fat diet. Mollica et al. also found out that the butyrate could reduce the production of ROS, weaken the oxidative stress, and regulate mitochondrial biological efficiency and functional state, by activating AMPK/ACC pathway, thereby reducing liver fat.

An expression trouble in the mitochondrial gene has a long-term effect on energy metabolism. The butyric acid can significantly up regulate the mRNA expression of mitochondrial β-oxidation related genes Acc1 and Cpt1α, and the expression of decoupling-related key genes Ucp2, as well as the mRNA level of eight genes encoded by mitochondria themselves.

qRT-PCR analysis for mRNA expression levels of the genes related with mitochondrial function in liver 

Summary

The problems of fatty liver occured in livestock and poultry are caused on the account of an excessive energy intaken or an abnormal metabolism, and results in the incomplete fat oxidation and oxidative stress. The fundamental reason of this phenomenon is the poor function performance of mitochondria, which can not effectively oxidize fat to release ATP, and reduce mitochondrial stress. After an intervention of butyric acid derivatives, the mitochondrial function now has been improved, the energy substances is completely oxidized, the supply of ATP is sufficient, the problem of fatty liver is solved, and the animals is possible to survive well.

From the aspect of metabolism kinetics, butyrate root metabolizes very fast in vivo, with a 6-minute time to reach the peak value in blood, it is difficult to maintain an effective dosage and action time. But when tributyrin was used, the concentration of butyrate root in blood reached the effect concentration within 15 minutes, and then increased continuously. At the time of 30 minutes, the content of tributyrin reached the peak, while butyrate root at the time of 45 minutes, and maintained the effect concentration until 3 hours after being used. So that enough doses of tributyrin and butyrate is possible to enter into bone marrow hematopoietic cells to promote hemoglobin synthesis, increase oxygen input, promote mitochondrial fusion and regeneration, enhance mitochondrial power, output more ATP, achieve life-saving, promote intestinal development, reduce fatty liver and many other effects.