Sex-associated preventive effects of low-dose aspirin on obesity and non-alcoholic fatty liver disease in mouse offspring with over-nutrition in utero

Abstract

Aspirin has been found to diminish hypertriglyceridemia and hyperglycemia in both obese rodents and patients with type 2 diabetes mellitus. We aim to test if and how low dose aspirin is able to prevent obesity and the progression of non-alcoholic fatty liver disease (NAFLD) in the high risk subjects. We used offspring mice with maternal over-nutrition as a high risk model of obesity and NAFLD. The offspring were given postnatal HF-diet and diethylnitrosamine (DEN) to induce obesity and NAFLD, and were treated with or without a low dose of aspirin for 12 weeks (ASP or CTL groups). Aspirin treatment reduced body weight gain, reversed glucose intolerance, and depressed hepatic lipid accumulation in female, but not in male mice. Female mice displayed re-sensitized Insulin/Akt signaling and overactivated AMPK signaling, with enhanced level of hepatic PPAR-γ, Glut4 and Glut2, while male mice only enhanced hepatic PPAR-α and PPAR-γ levels. The female ASP mice had inhibited p44/42 MAPK activity and enhanced Pten expression, while male displayed activated p38 MAPK signaling. Furthermore, the female but not the male ASP mice reduced Wnt signaling activity via both the epigenetic regulation of Apc expression and the posttranscriptional regulation of β-catenin degradation. In summary, our study demonstrated a sex-associated effect of low dose aspirin on obesity and NAFLD prevention in female but not in male mice.

Maternal obesity accelerated non‑alcoholic fatty liver disease in offspring mice by reducing autophagy

“…While, a large number of studies have also shown that the activation of AMPK signal pathway can reduce the deposition of lipid droplets and the occurrence of NAFLD. Zhou et al ( 42 ) found that a low dose of aspirin may reduce lipid droplet deposition via AMPK activation in the offspring of obese mothers. Devarajan et al ( 32 ) also reported that the occurrence of NAFLD in offspring with energy limitation during the perinatal period was related to AMPK changes.…”

Sex difference in liver diseases: How preclinical models help to dissect the sex-related mechanisms sustaining NAFLD and hepatocellular carcinoma

“…In particular, the authors observed that aspirin reduced Wnt-signaling activity via hypo-methylation of the APC gene which explains its anti-proliferative effect interacting with beta-catenin only in female mice. 205 …”

Ticagrelor, but Not Clopidogrel, Attenuates Hepatic Steatosis in a Model of Metabolic Dysfunction-Associated Steatotic Liver Disease

“…The administration of aspirin or acetaminophen was considered for the relief of the animals' pain. However, since there have been previous studies that showed that analgesics are effective in alleviating diseases in nonalcoholic fatty liver disease [13][14][15], this experiment was not used to confirm disease improvement through drug administration in liver disease animal models.…”