S-Equol improves type 2 diabetes mellitus combined with nonalcoholic fatty liver disease by regulating SREBP pathway and PPARγ in rats

To analyze the effects of S-Equol on glucose and lipid metabolism in rats with type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD).

Fifty SD rats aged 6 weeks were randomly divided into the control group (n=10) and the modeling group (n=40) after 1 week's adaptive feed. The modeling group was given high-fat and high-sugar diet combined with streptozotocin (STZ) intrabdominal injection to construct T2DM model. Rats whose fasting blood-glucose (FBG) level was greater than 11.1 mmol/L were randomly divided into the 4 groups: the model group, the S-Equol low-dose group (20 mg·kg^-1·d^-1), the S-Equol medium-dose group (40 mg·kg^-1·d^-1) and the S-Equol high-dose group (80 mg·kg^-1·d^-1). After 12 weeks of intervention, the level of serum total cholesterol (TC), triglyceride (TG), FBG, high density lipoprotein (HDL), low density lipoprotein (LDL), total bilirubin (TBIL), direct bilirubin (DBIL), total protein (TP), albumin (Alb) and globulin (Glb) were detected. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and liver interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were detected by ELISA. Peroxisome proliferator-activated receptor gamma (PPARγ), acetyl-CoA carboxylase (ACC), sterol regulatory element binding protein-1 (SREBP-1) and fatty acid synthetase (Fasn) expression levels related to lipid metabolism were detected by Western blotting and RT-qPCR.

Compared with the model group, the S-Equol low-dose group had significantly decreased levels of insulin resistance (P<0.05), the S-Equol medium-dose group had significantly decreased levels of insulin secretion (P<0.05), and the S-Equol low-and high-dose groups had obviously decreased levels of FBG (P<0.05); The S-Equol low-dose group had significantly decreased liver index, albumin/globulin ratio (A/G) and LDL (P<0.05), and the S-Equol medium-dose group had significantly decreased DBIL and ALT (P<0.05). Compared with the model group, the histological morphology of liver in the S-Equol low-, medium- and high-dose groups improved and the area of liver lipid deposition decreased obviously (P<0.05), and the S-Equol medium-dose group and the high-dose group had reduced liver inflammation (P<0.05). The results of Western blotting showed the expression of PPARγ and ACC in liver tissue of rats was significantly down-regulated by medium- and high-dose S-Equol intervention (P<0.05). The results of RT-qPCR showed that S-Equol intervention significantly could reduce the transcription levels of ACC, SREBP-1, Fasn and PPARγ in liver tissue of rats (P<0.05).

The intervention of S-Equol can reduce liver lipid deposition, lipid metabolism-related molecule expression and inflammation in T2DM rats with NAFLD, and the mechanism may be related to regulating SREBP pathway and PPARγ expression.