Abstract: OBJECTIVE To observe the differential regulation of berberine on PCSK9 and LDLR in liver and pancreas of hyperlipidemia mice, and to explore the new effect and mechanism of berberine on reducing hyperlipidemia and hyperinsulinemia. METHODS SPF grade C57BL/6J mice were randomly divided into 3 groups. The control group was fed with normal diet, the high fat diet group was fed with high fat diet, and the berberine group was given both high fat diet and berberine by gastric perfusion at the same time. Fasting blood glucose was measured by automatic glucose meter. Fasting serum insulin was measured by enzyme-linked immunosorbent assay(ELISA), and the ratio of blood glucose to insulin was calculated. Fasting serum PCSK9 level was measured by ELISA. The contents of triglyceride, total cholesterol, high density cholesterol and low density cholesterol in serum were determined by ELISA and corresponding kit. The morphological changes of liver and pancreas were observed by HE staining. The expressions of PCSK9 and LDLR proteins in liver and pancreas were detected by Western blotting. RESULTS Berberine could reduce cholesterol content in serum, PCSK9 content in plasma, PCSK9 protein expression of liver, and increase LDLR protein expression on liver surface. It could improve insulin resistance induced by high fat diet, reduce the number of hypertrophy and vacuoles of islet cells, increase the expression of PCSK9 protein on pancreatic surface, and decrease the expression of LDLR protein on pancreatic surface. CONCLUSION Berberine regulates the expression and secretion of PCSK9 in high fat diet mice with tissue specificity, enhance LDLR-mediated cholesterol cell uptake in liver and inhibiting LDLR-mediated cholesterol uptake in pancreas, thereby improving liver fatty disease and insulin resistance induced by high fat diet.