Effect of berberine on expression of hepatocyte nuclear factor-4α in rats with fructose-induced insulin resistance

Abstract

The effects of berberine on the expression of hepatocyte nuclear factor-4α (HNF-4α) in liver of rats with fructose-induced insulin resistance and the molecular mechanism of berberine preventing insulin resistance were investigated. The experimental animals were divided into two groups of 16 animals each. The control group received a control routine diet containing 60% carbohydrate, and the study group a high-fructose diet containing 60% fructose as the sole source of carbohydrate. At the end of 6 weeks these were each subdivided into two groups. One was administered with berberine [187.5 mg/(kg·d) in 5 g/L carboxymethyl cellulose] by intragastric intubation and the other group was treated with a vehicle (5 g/L carboxymethyl cellulose). The rats were fed on the same dietary regimen for the next 4 weeks. After the experimental period of 10 weeks, plasma glucose, insulin and triglyceride levels were measured. HOMA insulin resistance index (HOMA-IR) was assayed. Immunohistochemistry, semiquantitative RT-PCR and western blot were used to detect the expression of HNF-4α in liver. Compared with control diet, fructose feeding induced hyperinsulinemia, HOMA-IR and increased triglyceride (all P<0.01). Berberine prevented the rise in plasma insulin (P<0.01), HOMA-IR (P<0.01) and triglyceride (P<0.05) in the fructose-fed rats. No change in plasma glucose was seen among these groups. The mRNA and protein expression of HNF-4α was decreased in the fructose-fed rats, but berberine could promote its expression. It was concluded that berberine could prevent fructose-induced insulin resistance in rats possibly by promoting the expression HNF-4α in liver.

Keywords

insulin resistance / berberine / liver / HNF-4α / high fructose diet

References

[1] LengS. H., LuF. E., XuL. J.. Therapeutic effects of berberine in impaired glucose tolerance rats and its influence on insulin secretion. Acta Pharmacol Sin, 2004, 25: 496-502

[2] LeeY. S., KimW. S., KimK. H., et al.. Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states. Diabetes, 2006, 55(8): 2256-2264

[3] ZhouZ., KangX., JiangY., et al.. Preservation of hepatocyte nuclear factor-4alpha is associated with zinc protection against TNF-alpha hepatotoxicity in mice. Exp Biol Med (Maywood), 2007, 232(5): 622-628

[4] HsiehP. S.. Reversal of fructose-induced hypertension and insulin resistance by chronic losartan treatment is independent of AT2 receptor activation in rats. J Hypertension, 2005, 23: 2209-2217

[5] OlatunjiL. A., SoladoyeA. O.. Increased magnesium intake prevents hyperlipidemia and insulin resistance and reduces lipid peroxidation in fructose-fed rats. Pathophysiology, 2007, 14: 11-15

[6] IharaA., YamagataK., NammoT., et al.. Functional characterization of the HNF4alpha isoform (HNF4alpha8) expressed in pancreatic beta-cells. Biochem Biophys Res Commun, 2005, 329(3): 984-990

[7] PrietoP. G., CancelasJ., MorenoP., et al.. Effects of diet supplementation with olive oil and guar upon fructose-induced insulin resistance in normal rats. Endocrine, 2007, 31: 294-299

[8] OyadomariS., MatsunoF., ChowdhuryS., et al.. The gene for hepatocyte nuclear factor (HNF)-4α is activated by glucocorticoids and glucagon, and repressed by insulin in rat liver. FEBS Lett, 2000, 478: 141-146

[9] PrieurX., SchaapF. G., CosteH., et al.. Hepatocyte nuclear factor-4alpha regulates the human apolipoprotein AV gene: identification of a novel response element and involvement in the control by peroxisome proliferator-activated receptor-gamma coactivator-lalpha, AMP-activated protein kinase, and mitogen-activated protein kinase pathway. Mol Endocrinol, 2005, 19(12): 3107-3125

[10] BrusqJ. M., AncellinN., GrondinP., et al.. Inhibition of lipid synthesis through activation of AMP kinase: an additional mechanism for the hypolipidemic effects of berberine. J Lipid Res, 2006, 6: 1281-1288