Details

Autor(en) / Beteiligte

• Zhou, Jian
• Zhao, Yang
• Guo, Ya-Jing
• Zhao, Ya-Shuo
• Liu, Han
• Ren, Jing
• Li, Jie-Ru
• Ji, En-Sheng

Titel

A rapid juvenile murine model of nonalcoholic steatohepatitis (NASH): Chronic intermittent hypoxia exacerbates Western diet-induced NASH

Ist Teil von

• Life Sciences, 2021-07, Vol.276, p.119403-119403, Article 119403

Ort / Verlag

Netherlands: Elsevier Inc

Erscheinungsjahr

2021

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Many dietary NASH models require a long duration to establish (4–6 months). Chronic intermittent hypoxia (CIH), a cardinal hallmark of obstructive sleep apnea (OSA), may accelerate the progression of pediatric nonalcoholic fatty liver disease (NAFLD). However, diet-induced obese (DIO) mice exposed to CIH have not been perceived as a fast or reliable tool in NASH research. This study was designed to establish a rapid juvenile murine NASH model, and determine whether the combination of CIH and a western-style diet (hypercaloric fatty diet plus high fructose) can fully display key pathologic features of NASH. C57BL/6 N mice (3 weeks old) fed a control diet or western diet (WD) were exposed to CIH (9% nadir of inspired oxygen levels) or room air for 6 and 12 weeks. The Control/CIH group mainly exhibited hyperinsulinemia and insulin resistance (IR). In contrast, mice fed a WD developed weight gain after 3 weeks, microvesicular steatosis in 6 weeks, and indices of metabolic disorders at 12 weeks. Furthermore, CIH exposure accelerated WD- induced macromicrovesicular steatosis (liver triglycerides and de novo lipogenesis), liver injury (ballooned hepatocytes and liver enzymes), lobular/portal inflammation (inflammatory cytokines and macrophage recruitment), and fibrogenesis (hydroxyproline content and TGF-β protein). Notably, only the WD/CIH group exhibited elevated hepatic MDA content, protein levels of NOX4, α-SMA and collagen I, as well as reduced Nrf2 and HO-1 protein expression. WD/CIH treatment rapidly mimics the histological characteristics of pediatric NASH with metabolic dysfunction and fibrosis, representing an appropriate experimental model for NASH research.