PPARα agonist and metformin co-treatment ameliorates NASH in mice induced by a choline-deficient, amino acid-defined diet with 45% fat

Autor:	Kota Yano, Hideki Fujii, Takeshi Okanoue, Michihisa Moriguchi, Junji Kamon, Kohichiroh Yasui, Aya Takahashi, Yu Liu, Keiichiroh Okuda, Daiki Takahashi, Atsushi Umemura, Yoshito Itoh, Seita Kataoka, Kanji Yamaguchi, Yusuke Ito, Nozomi Tochiki, Yuya Seko, Hiroshi Ishiba, Shinya Okishio
Jazyk:	angličtina
Rok vydání:	2020
Předmět:	0301 basic medicine Male Peroxisome proliferator-activated receptor lcsh:Medicine Nicotinamide adenine dinucleotide Antioxidants chemistry.chemical_compound 0302 clinical medicine Non-alcoholic Fatty Liver Disease Choline Amino Acids lcsh:Science Non-alcoholic steatohepatitis Liver injury chemistry.chemical_classification Multidisciplinary Anti-Inflammatory Agents Non-Steroidal Alanine Transaminase Endoplasmic Reticulum Stress Metformin Choline Deficiency Butyrates 030211 gastroenterology & hepatology Drug Therapy Combination medicine.drug Agonist medicine.medical_specialty medicine.drug_class Article 03 medical and health sciences Internal medicine medicine Animals PPAR alpha Aspartate Aminotransferases Phenylurea Compounds lcsh:R AMPK nutritional and metabolic diseases medicine.disease Diet Fibroblast Growth Factors Mice Inbred C57BL Disease Models Animal 030104 developmental biology Endocrinology chemistry lcsh:Q NAD+ kinase
Zdroj:	Scientific Reports, Vol 10, Iss 1, Pp 1-11 (2020) Scientific Reports
ISSN:	2045-2322
DOI:	10.1038/s41598-020-75805-z
Popis:	We explored the beneficial effects of GW7647, a peroxisome proliferator activated receptor α (PPARα) agonist, and metformin, an anti-diabetic drug on an advanced nonalcoholic steatohepatitis (NASH) model in rodents and investigated the possible mechanisms involved. Mice were fed control chow or a choline-deficient l-amino acid-defined diet containing 45% fat (HF-CDAA). The mice fed HF-CDAA diets for 16 weeks were divided into four groups: the no treatment (HF-CDAA), HF-CDAA containing 1000 mg/kg metformin, HF-CDAA containing 10 mg/kg GW7647, and HF-CDAA with both metformin and GW7647 groups. Metformin alone slightly deteriorated the aspartate and alanine aminotransferase (AST/ALT) values, whereas co-treatment with GW7647 and metformin greatly suppressed liver injury and fibrosis via activation of the AMP-activated protein kinase (AMPK) pathway. Further study revealed that co-treatment decreased the expression of inflammatory-, fibrogenesis-, and endoplasmic reticulum (ER) stress-related genes and increased the oxidized nicotinamide adenine dinucleotide (NAD)/reduced nicotinamide adenine dinucleotide (NADH) ratio, suggesting the superiority of co-treatment due to restoration of mitochondrial function. The additive benefits of a PPARα agonist and metformin in a HF-CDAA diet-induced advanced NASH model was firstly demonstrated, possibly through restoration of mitochondrial function and AMPK activation, which finally resulted in suppression of hepatic inflammation, ER stress, then, fibrosis.
Databáze:	OpenAIRE
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