Vitamin B5 and N-Acetylcysteine in Nonalcoholic Steatohepatitis: A Preclinical Study in a Dietary Mouse Model

Abstract

Background Nonalcoholic fatty liver disease (NAFLD) is the number one cause of chronic liver disease and second indication for liver transplantation in the Western world. Effective therapy is still not available. Previously we showed a critical role for caspase-2 in the pathogenesis of nonalcoholic steatohepatitis (NASH), the potentially progressive form of NAFLD. An imbalance between free Coenzyme A (CoA) and acyl-CoA ratio is known to induce caspase-2 activation. Objectives We aimed to evaluate CoA metabolism and the effects of supplementation with CoA precursors, pantothenate and cysteine, in mouse models of NASH. Methods CoA metabolism was evaluated in methionine-choline deficient (MCD) and Western diet mouse models of NASH. MCD-diet fed mice were treated with pantothenate and N-acetylcysteine or placebo to determine effects on NASH. Results Liver free CoA content was reduced, pantothenate kinase (PANK), the rate-limiting enzyme in the CoA biosynthesis pathway, was down-regulated, and CoA degrading enzymes were increased in mice with NASH. Decreased hepatic free CoA content was associated with increased caspase-2 activity, and correlated with worse liver cell apoptosis, inflammation and fibrosis. Treatment with pantothenate and N-acetylcysteine did not inhibit caspase-2 activation, improve NASH, normalize PANK expression, or restore free CoA levels in MCD diet-fed mice. Conclusion In mice with NASH, hepatic CoA metabolism is impaired, leading to decreased free CoA content, activation of caspase-2, and increased liver cell apoptosis. Dietary supplementation with CoA precursors did not restore CoA levels or improve NASH, suggesting that alternative approaches are necessary to normalize free CoA during NASH.

L-carnitine supplementation attenuates NAFLD progression and cardiac dysfunction in a mouse model fed with methionine and choline-deficient diet

“…5D), suggestive of its inhibitory effect against fibrogenic ␣SMA-producing cells. Furthermore, at the hepatic level, the anti-fibrotic effect of LC was confirmed from the level of caspase-2 protein, which is thought to be a marker of NASH [6,8]. Caspase-2 level increases based on the stages of fibrosis both in animals and humans.…”

“…The initial fat accumu-lation in the liver results in the activation of multiple cellular stress pathways and induces the generation of reactive oxygen species (ROS), which in turn causes the transdifferentiation of hepatic stellate cells into activated myofibroblasts expressing ␣-smooth muscle actin (␣SMA) [3][4][5]. Some authors have recently proposed caspase-2 as a new NASH marker, as its expression increases with the worsening of fibrosis in humans and animal models of NASH [6][7][8].…”

Grape Leucoanthocyanidin Protects Liver Tissue in Albino Rabbits with Nonalcoholic Hepatic Steatosis

“…Due to the increased risk of disease associated with these drugs, alternative substances such as betaine [Abdelmalek et al, 2009], N-acetylcysteine [Emel Pamuk and Sonsuz, 2003;Khoshbaten et al, 2010;Machado et al, 2016], and vitamin E [Sanyal et al, 2010] have been studied, but also yielded poor results.…”

Protective effect of N-acetylcysteine activated carbon release microcapsule on myocardial ischemia-reperfusion injury in rats

“…With regard to the heart, NAC may improve the systolic function of myocardial cells and cardiac function, resist myocardial apoptosis, protect ventricular remodeling and vascular remodeling, reduce opiomelanocortin levels in the serum and improve the content of nitric oxide (NO) in the serum, and thus improve vascular endothelial function ( 29 – 33 ). Therefore, NAC has strong pharmacological effects ( 34 , 35 ), though its unfavorable effects include its relatively fast metabolism in the body, large clinical dose and low bioavailability, and side effects such as flush, nausea and vomiting ( 35 – 37 ). By contrast, medicinal activated carbons are sufficiently absorbed and biocompatible ( 35 ), and slowly release drugs during the metabolism of absorbed drugs, which overcomes the limitations of acetylcysteine and improves drug action time and bioavailability ( 38 ).…”