Maintaining cholesterol homeostasis: Sterol regulatory element-binding proteins

The molecular mechanism of how hepatocytes maintain cholesterol homeostasis has become much more transparent with the discovery of sterol regulatory element binding proteins (SREBPs) in recent years. These membrane proteins aremembers of the basic helix-loop-helix-leucine zipper (bHLHZip) family of transcription factors. They activate the expression of at least 30 genes involved in the synthesis of cholesterol and lipids. SREBPs are synthesized as precursor proteins in the endoplasmic reticulum (ER), where they form a complex with another protein, SREBP cleavage activating protein (SCAP). The SCAP molecule contains a sterol sensory domain. In the presence of high cellular sterol concentrations SCAP confines SREBP to the ER. With low cellular concentrations, SCAP escorts SREBP to activation in the Golgi. There, SREBP undergoes two proteolytic cleavage steps to release the mature, biologically active transcription factor, nuclear SREBP (nSREBP). nSREBP translocates to the nucleus and binds to sterol response elements (SRE) in the promoter/enhancer regions of target genes. Additional transcription factors are required to activate transcription of these genes. Three different SREBPs are known, SREBPs-1a, -1c and -2. SREBP-1a and -1c are isoforms produced from a single gene by alternate splicing. SREBP-2 is encoded by a different gene and does not display any isoforms. It appears that SREBPs alone, in the sequence described above, can exert complete control over cholesterol synthesis, whereas many additional factors (hormones, cytokines, etc.) are required for complete control of lipid metabolism. Medicinal manipulation of the SREBP/SCAP system is expected to prove highly beneficial in the management of cholesterol-related disease.

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.