Hepatic steatosis is a risk factor for liver cirrhosis and atherosclerosis. Both the liver and adipocytes play a major role in the regulation of cellular and circulating serum lipids, predominantly triglyceride and cholesterol. In our previous studies, fenugreek decreased the hepatic triglyceride and total cholesterol levels in normal rats fed with a high-fat high-sucrose diet [13, 14]. The present study investigated dose-dependent effects of fenugreek and its safety and tolerability.
The body weight gain and EWAT and IBAT weights in the VH group decreased significantly as compared with all of the other groups. In a pair feeding procedure, the VH group showed slightly less food intake than the other groups. It has been reported that the reduced food intake in the presence of soluble fibers such as galactomannan contained in fenugreek was caused by delaying gastric emptying and promoting satiety. In our study, the ratio of body weight gain to food intake was similar among the groups . However, the VH group showed significant lower levels of the energy efficiency ratio (EER) compared to the Ctrl group. Therefore, we suspect that the decreases in body and tissue weight were caused by the decrease of EER rather than the decrease in energy intake.
Fenugreek dose-dependently reduced the hepatic triglyceride and total cholesterol levels. Whereas the fecal triglyceride excretion levels rose significantly only in the VH group, fenugreek dose-dependently augmented the fecal total cholesterol and the bile acid excretion levels. The plasma triglyceride and total cholesterol levels were not significantly different among the groups. These results suggest that the mechanism underlying the inhibition of lipid accumulation in the liver and the adipose tissue would have enhanced the total cholesterol and the bile acid excretion in feces. Likewise, the increase of triglyceride excretion led to these results in the VH group.
Saponins, such as diosgenin contained in fenugreek, form large micells from bile acid and saponin molecules in the small intestine, and these micelles inhibit the cholesterol absorption by directly excreting cholesterol in feces [15, 16]. Diosgenin also reduces the triglyceride content and mRNA expression levels of lipogenic genes (FAS, SCD-1 and ACC) and suppresses LXRα transactivation. This leads to down-regulation of both the mRNA and protein expression levels of SREBP-1c in HepG2 cells . These results obtained from the previous reports supported that fenugreek attenuated lipid accumulation in the liver by down-regulating lipid synthesis as well as increasing lipid excretion in the feces.
The fasting blood glucose levels decreased significantly in the M and VH groups as compared with the Ctrl group, but the fasting plasma insulin levels did not differ significantly among the fenugreek-administered groups as compared with the Ctrl group. HOMA-IR was not significantly different among the groups. Therefore, in these experiments, fenugreek did not affect the glucose tolerance. However, some improving effects on the glucose metabolism and glucose tolerance of fenugreek have been reported. For example, 4-hydroxyisoleucin contained in fenugreek stimulates insulin secretion [2, 18]. In OGTT in our experiment, the fenugreek administration did not significantly change the plasma insulin levels or blood glucose levels except at 120 min in the VH group. Further, fenugreek inhibited insulin secretion only in the VH group. It has been reported that fenugreek also enhances insulin sensitivity through the activation of insulin signaling at an early stage in peripheral tissues and liver . This effect is brought by the activation of glucose and lipid metabolism with up-regulation of several enzymes [19–23] and the increase of glycogen synthesis in the muscle and liver [22–24]. In addition, diosgenin enhances the peroxisome proliferator-activated receptor-γ (PPARγ) level in EWAT and promotes both the adipocyte differentiation and the size reduction. As a result, the secretion of monocyte chemoattractant protein-1 (MCP-1) in adipocytes is suppressed, while the secretion of adiponectin is promoted, and the inflammation in adipose tissue is inhibited [18, 25]. Therefore, we assume that fenugreek activated firstly insulin sensitivity rather than insulin secretion in the relatively mild metabolic disorders we generated in rats through high-fat high-sucrose diets. The VH group showed appetite reduction and diarrhea, while no rats in the M group showed any adverse effects or symptoms.
These results suggest that fenugreek dose-dependently inhibited lipid accumulation in the liver by increasing the lipid and bile acids excretion in the feces, and that an effective, safe and tolerable dose of fenugreek was around 2.50% (w/w).