Atorvastatin ameliorates α-KGDH and GDH functions in rats with diet-induced hypercholesterolemia

IF 2.5 4区医学 Q3 PHARMACOLOGY & PHARMACY Fundamental & Clinical Pharmacology Pub Date : 2025-04-07 DOI:10.1111/fcp.70009

Malgorzata Ewa Belczyk, Malgorzata Elzbieta Knapik-Czajka, Jagoda Maria Drag, Anna Gawedzka, Angelika Bal

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Abstract

Background

α-ketoglutarate dehydrogenase complex (α-KGDH) belongs to mitochondrial 2-oxoacid dehydrogenases family and is the key regulatory enzyme of cell metabolism. It is functionally interconnected with glutamate dehydrogenase (GDH) which is a source of α-KG, a substrate for α-KGDH. Our previous studies demonstrated that simvastatin had an influence on 2-oxoacid dehydrogenases, including α-KGDH. Hence, we hypothesised that atorvastatin, one of the most commonly prescribed lipid-lowering drugs, may modify liver α-KGDH and GDH.

Objectives

The purpose of the present study was to evaluate the effect of atorvastatin on liver α-KGDH and GDH in rats with diet-induced hypercholesterolemia.

Methods

Atorvastatin at dose 20 mg/kg b.wt. (HC + A group, n = 10) or vehicle (HC group, hypercholesterolemic control, n = 10) were administered to rats with hypercholesterolemia for 21 days. The normal control group was fed a standard diet (ST group, normal control, n = 10). α-KGDH and GDH activities as well as their protein levels were determined. Moreover, serum parameters of lipid profile and liver function were measured.

Results

Liver α-KGDH and GDH activities were lower in HC than in ST rats. Atorvastatin enhanced the inhibited activities of α-KGDH and GDH. Stimulation of α-KGDH and GDH by atorvastatin did not correspond with the increase in protein levels of these enzymes indicating that atorvastatin activated α-KGDH and GDH most likely via post-translational mechanism. Atorvastatin had a beneficial effect on serum lipid profile and did not change the parameters of liver function.

Conclusion

The present study demonstrated that atorvastatin ameliorated liver α-KGDH and GDH functions in rats with diet-induced hypercholesterolemia.

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阿托伐他汀改善饮食性高胆固醇血症大鼠α-KGDH和GDH功能

α-酮戊二酸脱氢酶复合物（α-KGDH）属于线粒体2-氧酸脱氢酶家族，是细胞代谢的关键调控酶。它在功能上与谷氨酸脱氢酶（GDH）相互连接，后者是α-KG的来源，α-KGDH的底物。我们之前的研究表明辛伐他汀对2-氧酸脱氢酶有影响，包括α-KGDH。因此，我们假设最常用的降脂药物之一阿托伐他汀可能会改变肝脏α-KGDH和GDH。目的观察阿托伐他汀对饮食性高胆固醇血症大鼠肝脏α-KGDH和GDH的影响。方法阿托伐他汀20 mg/kg b.wt。高胆固醇血症大鼠（HC + A组，n = 10）或对照（HC组，控制高胆固醇血症，n = 10）给予21 d。正常对照组饲喂标准饲粮（ST组为正常对照组，n = 10）。测定α-KGDH和GDH活性及其蛋白水平。同时测定血脂、肝功能等血清指标。结果HC大鼠肝脏α-KGDH和GDH活性低于ST大鼠。阿托伐他汀可增强α-KGDH和GDH的抑制活性。阿托伐他汀对α-KGDH和GDH的刺激与这些酶蛋白水平的升高不一致，表明阿托伐他汀激活α-KGDH和GDH很可能是通过翻译后机制。阿托伐他汀对血脂有有益的影响，对肝功能参数没有改变。结论阿托伐他汀可改善饮食性高胆固醇血症大鼠肝脏α-KGDH和GDH功能。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Fundamental & Clinical Pharmacology 医学-药学

CiteScore

5.30

自引率

6.90%

发文量

111

审稿时长

6-12 weeks

期刊介绍： Fundamental & Clinical Pharmacology publishes reports describing important and novel developments in fundamental as well as clinical research relevant to drug therapy. Original articles, short communications and reviews are published on all aspects of experimental and clinical pharmacology including: Antimicrobial, Antiviral Agents Autonomic Pharmacology Cardiovascular Pharmacology Cellular Pharmacology Clinical Trials Endocrinopharmacology Gene Therapy Inflammation, Immunopharmacology Lipids, Atherosclerosis Liver and G-I Tract Pharmacology Metabolism, Pharmacokinetics Neuropharmacology Neuropsychopharmacology Oncopharmacology Pediatric Pharmacology Development Pharmacoeconomics Pharmacoepidemiology Pharmacogenetics, Pharmacogenomics Pharmacovigilance Pulmonary Pharmacology Receptors, Signal Transduction Renal Pharmacology Thrombosis and Hemostasis Toxicopharmacology Clinical research, including clinical studies and clinical trials, may cover disciplines such as pharmacokinetics, pharmacodynamics, pharmacovigilance, pharmacoepidemiology, pharmacogenomics and pharmacoeconomics. Basic research articles from fields such as physiology and molecular biology which contribute to an understanding of drug therapy are also welcomed.