Maternal obstructive sleep apnea aggravates metabolic dysfunction-associated fatty liver disease via HMGB1-TLR4 signaling-mediated endoplasmic reticulum stress in male offspring rats

Abstract

Aims/hypothesis: Maternal obstructive sleep apnea (MOSA) may inflict long-term metabolic effects on offspring. We hypothesize that MOSA increases the propensity for metabolic dysregulation in offspring and thus facilitates the development of metabolic dysfunction-associated fatty liver disease (MAFLD). This study aims to test the hypothesis and explore the underlying mechanism.

Methods: The MOSA rat model of upper airway obstruction was established and fecundated. The postweaning male offspring (n = 171) from both the control group and MOSA group were randomly fed the normal chow diet (NCD, n = 89) or high-fat diet (HFD, n = 82) for the next 5 months. Liver function, lipid profile, glucose, and insulin levels were measured. Expression levels of fibrosis-related proteins and endoplasmic reticulum (ER) stress-related proteins in liver tissues were assessed using immunohistochemistry and western blotting.

Results: MOSA increased body and liver weight in male offspring, along with augmented liver organ coefficient. Serum levels of aminotransferases, low-density lipoprotein, high-density lipoprotein, triglycerides, total cholesterol, total bile acid, fasting glucose, and insulin increased significantly. MOSA exacerbated HFD-induced hepatic steatosis and fibrosis. These effects were driven by the overactivated double-stranded RNA-activated protein kinase (PKR)-like eukaryotic initiation factor 2(PERK)-activating transcription factor (ATF)4-C/EBP homologous protein (CHOP) signaling pathway-induced ER stress, and hyperacetylation and release of high mobility group box-1(HMGB1) elicited above signaling in a TLR4-dependent manner.

Conclusions: These findings indicate that MOSA can exert prolonged adverse effects manifested as metabolic dysfunction in male offspring. Therefore, surveillance and management of OSA during pregnancy may be necessary to prevent and alleviate MAFLD in offspring.

Keywords: Endoplasmic reticulum stress; High mobility group box-1; Metabolic dysfunction-associated fatty liver disease; Obstructive sleep apnea; PERK-ATF4-CHOP.