Abstract
Ketosis is a condition where ketone bodies are produced as an alternative energy source, due to insufficient glucose for energy production so that the body switches from carbohydrate metabolism to mostly fat metabolism. In this study, we examined the anti-ketosis effects of silibinin, a major active component of silymarin. We induced ketosis in FL83B mouse hepatocytes in vitro by culturing in low glucose media and compared results to hepatocytes maintained in high-glucose conditions. We quantified β-hydroxybutyrate (BHB) levels with a colorimetric assay. In low-glucose conditions, silibinin reduced the amount of BHB produced, compared to high-glucose conditions; thus, silibinin exhibited an anti-ketotic effect. Ketone body formation during beta oxidation is mediated by 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2). The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) regulates the transcription of HMGCS2, and plays a vital role in BHB levels. We showed that silibinin inhibited the expression of HMGCS2 and NF-kB at transcriptional and translational levels. Silibinin also inhibited the nuclear translocation of NF-kB and its DNA binding activity. To elucidate the relationship between HMGCS2 and NF-kB, we tested inhibited and over-expressed NF-kB. We found that NF-kB acted as a positive regulator for HMGCS2 under ketosis treatment conditions.
Highlights
Induction of in vitro ketosis is a convenient method for testing the efficacy of specific drugs designed to treat ketosis and for determining the molecular targets involved
We analyzed its activity on hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) and NFkB, and we explored the possibility of targeting the HMGCS2/nuclear factor kappa-light-chainenhancer of activated B cells (NF-kB) pathway in the development of treatments for ketosis
The results showed that silibinin reduced BHB levels compared to the levels observed in ketosis
Summary
Induction of in vitro ketosis is a convenient method for testing the efficacy of specific drugs designed to treat ketosis and for determining the molecular targets involved. Ketosis can be treated with natural substances without side effects. In dairy cows, these substances can be mixed into the feed. Natural products that reduce ketone body concentrations to below 0.5 mM (ketotic conditions), with no adverse effects at the required concentrations, are considered suitable antiketotic drugs. Silibinin has shown pharmacological effects, due to its structure, which consists of two diastereomers, silybin A, and silybin B (Davis-Searles et al 2005). Silibinin showed effective pharmacological activity in the liver, when it was used as a supportive element for alcoholic treatments and when it was used to treat child grade BA^ liver cirrhosis (Saller et al 2008). Silibinin is an anti-cancer drug; it has shown high efficacy
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