Association of SREBP2 gene polymorphisms with the risk of osteonecrosis of the femoral head relates to gene expression and lipid metabolism disorders.

Although lipid metabolism disorders have been recognized as a primary factor of osteonecrosis of the femoral head (ONFH), the molecular pathogenesis remains unclear. Sterol regulatory element­binding protein 2 (SREBP2) specifically regulates cholesterol and fatty acid metabolism to maintain lipid homeostasis. To explore the roles of the SREBP2 gene in the development of ONFH, the authors analyzed the gene polymorphism and gene expression of three tag single nucleotide polymorphisms of the SREBP2 gene, the serum lipids levels, and their associations with ONFH development in 182 ONFH patients and 179 healthy controls. The results demonstrated that the stage IV proportions of ONFH patients carrying the rs2267439CT or CC genotype were significantly higher and lower than the stage III proportions of ONFH patients (P=0.039), respectively. The serum triglyceride, low­density lipoprotein (LDL)­c levels, and LDL­C/high­density lipoprotein (HDL)­C ratio in the ONFH group were significantly increased compared to those in the control group (P=0.01, P=0.005, P=0.0001) while the HDL­C level of ONFH group was remarkably lower than that of the control group (P=0.0001). Association analysis further revealed that the LDL­c levels of the rs226744 GG and AG genotype carriers were statistically higher than that of the AA genotype carriers (P=0.039, P=0.05). These results demonstrated that the gene polymorphism of SREBP2 not only significantly associated with the clinical phenotypes of ONFH but also closely related to lipid metabolism disorder. The results indicated that SREBP2 gene polymorphism and function may play key roles in the development of ONFH.

Circulating PCSK9 affects serum LDL and cholesterol levels more than SREBP-2 expression.

BACKGROUND: Cholesterol homeostasis is dependent upon the sterol regulatory element binding protein 2 (SREBP-2) regulatory system and the functioning of plasma proprotein convertase subtilisin/kexin type 9 (PCSK9). Many studies have also reported that low density lipoprotein receptor (LDLR) levels in cellular membranes are related to the functioning of these proteins. OBJECTIVES: The aim of this study was to investigate the association of lipid profiles with circulating PCSK9 protein values and SREBP-2 expression levels in normal subjects. MATERIAL AND METHODS: The study involved 120 randomly chosen healthy subjects. Their lipid profiles were measured using routine laboratory techniques, and the plasma PCSK9 protein and SREBP-2 expression levels were determined by ELISA and real time quantitative PCR methods, respectively. A statistical analysis was carried out using a statistical software package. RESULTS: Linear regression analyses showed a significant correlation between total cholesterol and PCSK9 (3.54 ± 1.31 ng/mL), as well as between total cholesterol and SREBP-2 (0.1-35.38) (p = 0.002 and p = 0.02, respectively). Furthermore, multiple regression analyses showed strict correlations between PCSK9 and cholesterol-related parameters especially the total cholesterol/HDL-C ratio (ß = 3.53, p = 0.001). There was no significant correlation between circulating PCSK9 and SREBP-2 expression levels (r = 1.2, p = 0.3). CONCLUSIONS: The study results revealed that serum cholesterol-related parameters are strictly associated with plasma PCSK9 values, suggesting that PCSK9 function has a greater effect on serum total cholesterol levels than SREBP-2 expression does. Furthermore, the total cholesterol/HDL-C ratio was a better indicator for evaluating PCSK9 level than total cholesterol.

Expression of Sterol Regulatory Element-Binding Proteins in epicardial adipose tissue in patients with coronary artery disease and diabetes mellitus: preliminary study.

Objectives: Sterol regulatory element-binding proteins (SREBP) genes are crucial in lipid biosynthesis and cardiovascular homeostasis. Their expression in epicardial adipose tissue (EAT) and their influence in the development of coronary artery disease (CAD) and type-2 diabetes mellitus remain to be determined. The aim of our study was to evaluate the expression of SREBP genes in EAT in patients with CAD according to diabetes status and its association with clinical and biochemical data. Methods: SREBP-1 and SREBP-2 mRNA expression levels were measured in EAT from 49 patients with CAD (26 with diabetes) and 23 controls without CAD or diabetes. Results: Both SREBPs mRNA expression were significantly higher in patients with CAD and diabetes (p<0.001) and were identified as independent cardiovascular risk factor for coronary artery disease in patients with type-2 diabetes (SREBP-1: OR 1.7, 95%CI 1.1-2.5, p=0.02; SREBP-2: OR 1.6, 95%CI 1.2-3, p=0.02) and were independently associated with the presence of multivessel CAD, left main and anterior descending artery stenosis, and higher total and LDL cholesterol levels, and lower HDL cholesterol levels, in patients with CAD and diabetes. Conclusions: SREBP genes are expressed in EAT and were higher in CAD patients with diabetes than those patients without CAD or diabetes. SREBP expression was associated as cardiovascular risk factor for the severity of CAD and the poor lipid control. In this preliminary study we suggest the importance of EAT in the lipid metabolism and cardiovascular homeostasis for coronary atherosclerosis of patients with diabetes and highlight a future novel therapeutic target.