| Type 2 diabetes is a metabolic syndrom charaterized as acarbohydrate,protein and lipid metabolism disorder due to insulin secretion deficiency and dysfunction.Most patients with diabetes presented as abnormal lipid metabolism, which is also the main cause of death in diabetic microvascular and macrovascular disease. It has beed reported that berberine could correct glucose and lipid disorders. Our previous work demonstrated that berberine can enter the hepatocyte nuclear factor inhibiting the expression of nuclear factors HNF4α, PGC-1, FOXO1 expression, with anti-hyperlipidemia effect and inhibition of gluconeogenesis, mi R122 as a liver-specific mi RNAs, subject to the regulation of nuclear factor HNF4α closely related to lipid metabolism. Based on the previous study, current study reveals HNF4α/mi R122 can be used as pharmacological target for glucose and lipid metabolism crosstalk, and berberine might regulate glucose and lipid disorder in type2 diabetes via inhibiting this target. Berberine poor absorption and bioavailability are low, resulting in limited clinical applications. In view of this shortcoming our group join capric acid sodium salt absorption enhancers, and Huang Gui solid dispersions were prepared, so that berberine can be improved poor absorption and low bioavailability characteristics. It has been patented.In our vivol experiment in the, STZ-induced type 2 diabetic mouse model was used, and it was been gived different dose of Berberine and Huang Gui solid dispersions. After 4 weeks, we examined fasting blood glucose, liver index,fasting insulin, oral glucose resistance volume, the mi R122 expression level in serum and liver tissue, and gluconeogenesis key enzymes(G6Pase and PEPCK) and lipid metabolism key proteins(SREBP-1/FAS/ACC ? /CPT-1) expression levels. Our results showed that Model group showed fasting blood glucose, liver index, oral glucose resistance volume and the mi R122 expression level in serum were obviouslyincreased, insulin level and high-density lipoprotein obviously reduced. HE staining displayed small rat liver leaflets deformation, and liver cable arranged disorder, and liver cell expansion big degeneration, also has local inflammation and necrosis phenomenon. HNF4α immune fluorescent results displayed intracellular HNF4αprotein and the nuclear of HNF4-α protein expression were significantly higher.Treatment with berberine for 4weeks, berberine high dose group and Huang Gui solid dispersions group can reduced fasting blood glucose, total cholesterol, and Triglyceride, and low density fat protein, and serum and liver organization in the mi122 expression obviously reduced. The results indicates that berberine could improve the glucose and lipid disorders in liver of type 2 diabetes via inhibition of liver HNF4α, gluconeogenesis key enzymes(G6Pase/PEPCK) and lipid metabolism key proteins(SREBP-1/FAS/ACCα) expression levels.Secondly, palmitic acid incubated Hep G2 cell was used as glucose and lipid metabolism disoeder cell model. HNF4α gene overexpression or silence with mi R122 mimic or inhibitor was used in the cell. The regulation of berberine on gluconeogenesis key enzymes(G6Pase/PEPCK) and lipid metabolism key proteins(SREBP-1/FAS/ACCα/CPT-1) were dected in cell.Treatment of PA-incubated Hep G2 cells for 24 h with berberine decreased expression of HNF4? and the micro RNA mi R122, the key gluconeogenesis enzymes Phosphoenolpyruvate carboxykinase(PEPCK) and Glucose-6-phosphatase(G6Pase)and the key lipid metabolism proteins Sterol response element binding protein-1(SREBP-1), Fatty acid synthase-1(FAS-1) and Acetyl-Coenzyme A carboxylase(ACC ?) and increased Carnitine palmitoyltransferase-1(CPT-1) compared to T2 D mice or PA-incubated Hep G2 cells. Expression of HNF4? in Hep G2 cells increased expression of gluconeogenic and lipid metabolism enzymes and BBR treatment or knock down of mi R122 attenuated the effect of HNF4 ? expression. In contrast,berberine treatment did not alter expression of gluconeogenic and lipid metabolism enzymes in Hep G2 cells with knockdown of HNF4 ?. In addition, mi R122 mimic increased expression of gluconeogenic and lipid metabolism enzymes in Hep G2 cells with knockdown of HNF4?. These data indicate that mi R122 is a critical regulator in the downstream pathway of HNF4? in the regulation of hepatic gluconeogenesis and lipid metabolism in Hep G2 cells. The effect of berberine on hepatic gluconeogenesisand lipid metabolism is mediated through HNF4 ? and is regulated downstream of mi R122. Our data provide new evidence to support HNF4 ? and mi R122 regulated hepatic gluconeogenesis and lipid metabolism as promising therapeutic targets for the treatment of T2 D.In summary, Huang Gui solid dispersions 40mg/kg and berberine 160mg/kg have the same therapeutic effect in the treatment of diabetes. This is the first study to investigate the effect of BBR on both HNF4? and mi R122 in the regulation of hepatic gluconeogenesis and lipid metabolism in Type 2 diabetes mellitus. Our data suggest that berberine exhibits a dual effect on maintenance of both glucose and lipid homeostasis through HNF4? regulated mi R122 expression. In addition, we suggest that the HNF4? regulated mi R122 pathway may be a key drug target for maintenance of glucose and lipid homeostasis in Type 2 diabetes mellitus. |
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