High-Efficacy α,β-Dehydromonacolin S Improves Hepatic Steatosis and Suppresses Gluconeogenesis Pathway in High-Fat Diet-Induced Obese Rats

Autor:	Vatcharin Rukachaisirikul, Chatchai Muanprasat, Acharaporn Duangjai, Chutima Srimaroeng, Atcharaporn Ontawong, Chittreeya Tansakul, Jutatip Kaewmalee
Rok vydání:	2021
Předmět:	medicine.medical_specialty type 2 diabetes mellitus Pharmaceutical Science Peroxisome proliferator-activated receptor lovastatin analog Article Proinflammatory cytokine Pharmacy and materia medica Insulin resistance Internal medicine α β-dehydromonacolin S Drug Discovery medicine Protein kinase B chemistry.chemical_classification hepatic steatosis statin Liver X receptor alpha 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor medicine.disease RS1-441 gluconeogenesis Endocrinology chemistry Gluconeogenesis Medicine Molecular Medicine Steatosis Phosphoenolpyruvate carboxykinase
Zdroj:	Pharmaceuticals, Vol 14, Iss 375, p 375 (2021) Pharmaceuticals Volume 14 Issue 4
ISSN:	1424-8247
DOI:	10.3390/ph14040375
Popis:	Isolated α,β-dehydromonacolin S (C5) from soil-derived fungus Aspergillus sclerotiorum PSU-RSPG178 was recently shown to exhibit an inhibitory effect against 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) activity in vitro. In this study, we investigated the effects of C5 on lipid-lowering, hepatic steatosis, and hepatic gluconeogenesis in vivo. The control rats received a daily dose of either vehicle or C5 at 10 mg/kg, while the high-fat diet-induced obese (HFD) rats were administered vehicle 1, 3, or 10 mg/kg C5 or 10 mg/kg lovastatin (LO) for 6 weeks. C5 significantly improved dyslipidemia and diminished liver enzymes, HMGR activity, insulin resistance, and hepatic steatosis, comparable to LO without any hepatotoxicity and nephrotoxicity in HFD rats. A higher efficacy of C5 in lipid-lowering activity and anti-hepatic steatosis was associated with a significant decrease in genes involved in lipid metabolism including sterol regulatory element binding protein (SREBP) 1c, SREBP2, liver X receptor alpha (LXRα), and peroxisome proliferator-activated receptor (PPAR) gamma (PPARγ) together with an increase in the PPAR alpha (PPARα). Correspondingly, C5 was able to down-regulate the lipid transporters cluster of differentiation 36 (CD36) and Niemann-Pick C1 Like 1 (NPC1L1), increase the antioxidant superoxide dismutase gene expression, and decrease the proinflammatory cytokines, tumor necrosis factor alpha (TNFα) and interleukin 1 beta (IL-1β). Impairment of hepatic gluconeogenesis and insulin resistance in HFD rats was restored by C5 through down-regulation of the gluconeogenic genes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), and the activation of AMP-dependent kinase serine (AMPK) and serine/threonine protein kinase B (Akt). Collectively, this novel C5 may be a therapeutic option for treating dyslipidemia, hepatic steatosis, and reducing potential risk for diabetes mellitus.
Databáze:	OpenAIRE
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