Microsomal triglyceride transfer protein inhibitor lomitapide-induced liver toxicity is ameliorated by Triiodothyronine treatment following improved bile homeostasis and ß-oxidation.
Toxicol Appl Pharmacol
; 434: 115825, 2022 01 01.
Article
em En
| MEDLINE
| ID: mdl-34902352
ABSTRACT
Dyslipidemia or its severe version like familial hypercholesterolemia causes a high risk for cardiovascular diseases. Lomitapide, a microsomal triglyceride transfer protein inhibitor, is approved to treat familial hypercholesterolemia, associated with liver fat accumulation. In this work, we investigated the effect of the combination of lomitapide and triiodothyronine (T3) in Zucker fatty rats. Lomitapide (1 mg/kg, PO), or T3 (13 µg/kg, PO), or their combination, were given to these rats once daily for fourteen days. Body weight and food intake were recorded once daily during the treatment period. Serum and hepatic lipids, glucose tolerance, serum aminotransferases, bile fluids, hepatic gene expression, and liver histology were assessed at the end of the treatment. Lomitapide treatment reduced body weight, food intake, glucose intolerance, and serum lipids, and elevated serum aminotransferases and liver lipids. When combined with T3, lomitapide showed an enhanced reduction in body weight, food intake, serum cholesterol, serum LDL, and glucose intolerance. The combination treatment increased bile flow rate and biliary cholesterol excretion rate. Combining T3 with lomitapide attenuated the elevation of serum aminotransferases and liver lipids. Hepatic ABCB11, ABCG5, ABCG8, CYP7A1, CPT1, and ACOX1 expressions were increased with combination treatment. Histological analysis indicated that T3 attenuated hepatic fat accumulation caused by lomitapide. These data suggests that combining lomitapide with T3 may reduce lomitapide-induced hepatic toxicity and provide additional benefits in obesity and glucose intolerance.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Tri-Iodotironina
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Benzimidazóis
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Ácidos e Sais Biliares
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Proteínas de Transporte
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Doença Hepática Induzida por Substâncias e Drogas
Limite:
Animals
Idioma:
En
Revista:
Toxicol Appl Pharmacol
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Índia