Background and aims: Low-grade chronic
inflammation plays an important role in the pathogenesis of
metabolic syndrome,
type 2 diabetes and their complications. In this study, we investigated the effects of
salsalate, a non-steroidal anti-inflammatory drug, on metabolic disturbances in an animal model of
prediabetes-a strain of non-obese hereditary hypertriglyceridemic (HHTg) rats. Materials and Methods: Adult male HHTg and Wistar control rats were fed a standard diet without or with
salsalate delivering a daily dose of 200 mg/kg of
body weight for 6 weeks. Tissue sensitivity to
insulin action was measured ex vivo according to basal and
insulin-stimulated 14C-U-glucose incorporation into muscle
glycogen or adipose tissue
lipids. The concentration of
methylglyoxal and
glutathione was determined using the HPLC-method. Gene expression was measured by quantitative RT-PCR. Results:
Salsalate treatment of HHTg rats when compared to their untreated controls was associated with significant amelioration of
inflammation,
dyslipidemia and
insulin resistance. Specificaly,
salsalate treatment was associated with reduced
inflammation, oxidative and dicarbonyl stress when inflammatory markers, lipoperoxidation products and
methylglyoxal levels were significantly decreased in serum and tissues. In addition,
salsalate ameliorated glycaemia and reduced serum
lipid concentrations.
Insulin sensitivity in visceral adipose tissue and skeletal muscle was significantly increased after
salsalate administration. Further,
salsalate markedly reduced hepatic
lipid accumulation (
triglycerides -29% and
cholesterol -14%). Hypolipidemic effects of
salsalate were associated with differential expression of genes coding for
enzymes and
transcription factors involved in
lipid synthesis (Fas, Hmgcr), oxidation (Pparα) and transport (Ldlr,
Abc transporters), as well as changes in gene expression of
cytochrome P450 proteins, in particular decreased
Cyp7a and increased
Cyp4a isoforms. Conclusion: These results demonstrate important anti-inflammatory and anti-oxidative effects of
salsalate that were associated with reduced
dyslipidemia and
insulin resistance in HHTg rats. Hypolipidemic effects of
salsalate were associated with differential expression of genes regulating lipid metabolism in the liver. These results suggest potential beneficial use of
salsalate in prediabetic patients with
NAFLD symptoms.