Valproic Acid-induced PPAR-alpha and FGF21 Expression Involves Survival Response in Hepatocytes|RISS 상세보기

다국어 초록 (Multilingual Abstract)

Hepatocyte damage caused by medications or herbal products is one of the important problem when these compounds are chronically administrated. Thus, improving hepatocyte survival during treatment offers a wide range of opportunities. Valproic acid (VPA), a branched short-chain fatty acid derived from naturally occurring valeric acid, is commonly used to treat epilepsy and seizures. Although VPA exerts numerous effects in cancer, HIV therapy, and neurodegenerative disease, its effects on the liver and its mechanism of action have not been fully elucidated. Here, we demonstrated that VPA caused moderate liver cell toxicity and apoptosis. Interestingly, VPA treatment increased transcription levels of PPAR alpha (PPAR-α) and fibroblast growth factor 21 (FGF21) in murine (Hepa1c1c7) hepatoma cells in a time and concentration dependent manner. VPA-induced FGF21 expression was significantly weaker under PPAR-α silencing condition than in cells transfected with non-targeting control siRNA. Subsequent experiments showed that cell viability was significantly lowered when the FGF21 signaling pathway was blocked by FGF receptor antagonist. Finally, we further determined that AMPK phosphorylation was not responsible for VPA-induced FGF21 expression and PPAR- increments. These results indicate that increases of FGF21 expression alleviate VPA-induced hepatic toxicity, thereby making FGF21 a potential biomarker for predicting liver damage during VPA treatments.

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참고문헌 (Reference)

1 Yan, A., "beta-Hydroxybutyrate upregulates FGF21 expression through inhibition of histone deacetylases in hepatocytes" 17 : 856-864, 2022

2 Ghodke-Puranik, Y., "Valproic acid pathway : pharmacokinetics and pharmacodynamics" 23 : 236-241, 2013

3 Avery, L. B., "Valproic acid is a novel activator of AMP-activated protein kinase and decreases liver mass, hepatic fat accumulation, and serum glucose in obese mice" 85 : 1-10, 2014

4 Ezhilarasan, D., "Valproic acid induced liver injury : An insight into molecular toxicological mechanism" 95 : 103967-, 2022

5 Khan, S., "Valproic acid improves glucose homeostasis by increasing beta-cell proliferation, function, and reducing its apoptosis through HDAC inhibition in juvenile diabetic rat" 30 : 438-446, 2016

6 Gottlicher, M., "Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells" 20 : 6969-6978, 2001

7 Sun, R., "Valproic acid attenuates skeletal muscle wasting by inhibiting C/EBPbetaregulated atrogin1 expression in cancer cachexia" 311 : C101-115, 2016

8 Zuo, S., "Valproic acid as a potentiator of metabolic syndrome in institutionalized residents on concomitant antipsychotics : fat chance, or slim to none?" 40 : 126-132, 2015

9 Leng, Y., "Valproic acid and other HDAC inhibitors upregulate FGF21 gene expression and promote process elongation in glia by inhibiting HDAC2and 3" 19 : 035-, 2016

10 Degirolamo, C., "Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23" 15 : 51-69, 2016