Effect of simvastatin on the expression of farnesoid X receptor in diabetic animal models of altered glucose homeostasis.
BACKGROUND
Statin therapy has affected glucose homoeostasis of type 2 diabetes patients, which could be related with bile acids metabolism. Whether bile acid metabolism and the expression of farnesoid X receptor (FXR), liver X receptor-α (LXR-α) and sterol regulatory element-binding protein (Srebp)-1c is regulated by hyperglycemia, or whether simvastatin therapy led to higher glucose is related with down-regulated expression of FXR in diabetic rats remained unclear.


METHODS
Forty male Wistar rats were randomly divided into four groups: normal control rats, insulin resistance rats, diabetic model rats, and the late simvastatin induced diabetic rats. Normal control rats were fed with standard diet, others were fed with high-fat diet. Diabetic model rats were induced by a single intraperitoneal injection of streptozotocin (STZ). The late simvastatin induced diabetic rats started simvastatin administration after STZ induced diabetic model rats. Characteristics of fasting blood glucose (FPG), lipid files and total bile acids (TBAs) were measured and the oral glucose tolerance test (OGTT) was performed after overnight fasting at the eighth weekend. RNA and protein levels of FXR, LXR-α and Srebp-1c were tested by Western blotting and reverse transcription polymerase chain reaction (RT-PCR).


RESULTS
The insulin resistance rats showed higher glucose, lipid files and lower expression of FXR compared with normal control rats (P > 0.05). The diabetic model rats showed significantly higher glucose, lipid files, TBA and lower expression of FXR compared with insulin resistance rats (P < 0.05). The late simvastatin induced diabetic rats displayed higher glucose and TBA and lower expression of FXR compared with diabetic model rats (P < 0.05).


CONCLUSIONS
Changes in bile acid homeostasis, including the alterations of bile acid levels and bile acid receptors, are either a cause or a consequence of the metabolic disturbances observed during diabetic models. Statin therapy induced hyperglycemia may be related with FXR, SHP, LXR-α and Srebp-1 pathways.
Department of Endocrinology, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, China.
Lulu
L
Wang
Department of Endocrinology, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, China.
Xianping
X
Huang
Department of Endocrinology, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, China.
Su
S
Hu
Department of Endocrinology, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, China.
Xiaoli
X
Ma
Department of Endocrinology, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, China.
Shaolian
S
Wang
Department of Endocrinology, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, China. Email: shuguangpang@163.com.
Shuguang
S
Pang
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006706:Homeostasis / Q000187:drug effects; D007333:Insulin Resistance / Q000502:physiology; D000071518:Liver X Receptors; D008297:Male; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019821:Simvastatin / Q000627:therapeutic use*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
D001786:Blood Glucose; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D019821:Simvastatin; D051780:Sterol Regulatory Element Binding Protein 1; D000099150:Receptor, Farnesoid X-Activated; C000605215:Nr1h3 protein, rat