Higher power exam confirmed the presence of multiple lipid droplets within the cytoplasm of hepatocytes from ISR2 transgenic mice. jejunal RNA from ISR2 mice showed a significant increase in genes involved in fatty acid and cholesterol synthesis. Cholesterol and triglyceride (TG) in jejunum and liver (mg/g protein) were significantly improved in ISR2 vs crazy type mice. Serum Cholesterol was significantly improved in VLDL and LDL fractions whereas the level of serum triglycerides was decreased in ISR2 vs crazy type mice. In conclusion, activation of intestinal SREBP2 only seems to be adequate to increase plasma cholesterol, highlighting the essential part of intestine in Rabbit polyclonal to alpha 1 IL13 Receptor keeping cholesterol homeostasis in the body. Introduction Elevated cholesterol level in the plasma is definitely a major risk element for atherosclerosis and coronary heart diseases . Cholesterol turnover in the body is definitely highly dynamic including influx and efflux processes across plasma membrane, intracellular trafficking and conversion to bile acids, de novo synthesis and intestinal absorption , . These processes are tightly regulated to maintain normal homeostasis in the body providing adequate supplies and avoiding excess of cholesterol . With respect to regulatory mechanisms, the Sterol Response Element Binding Proteins (SREBPs) have been shown to be central regulators of cholesterol and lipid homeostasis , . The SREBPs belong to a basic helix-loop-helix leucine zipper (bHLH-zip) family of transcription factors that are present in the endoplasmic reticulum as precursor transmembrane polypeptides associated with multi-protein complex that senses the level of cellular cholesterol . Cellular cholesterol depletion induces the translocation of SREBP precursor to the Golgi apparatus, where the NH2-terminus of 460 amino acids is then cleaved inside a multistep process and released as an active soluble transcription element . Three SREBP isoforms have been identified of which SREBP1a and 1c are transcribed from a single gene, whereas, SREBP2 is definitely a product of a distinct gene . The practical tasks of SREBPs have been extensively investigated in several cell tradition and animal models . These studies were based on either the activation of endogenous SREBPs by cholesterol depletion or the utilization of transgenic methods in mice by specifically deleting the genes or constitutively overexpressing the NH2-terminus active forms of SREBPs . These investigations yielded important information concerning the genes that are directly modulated by different SREBP isoforms and delineated the metabolic and physiological processes induced by their activation. For example, studies with liver-specific knockout and Orientin liver-specific overexpresison of the active forms of these regulatory proteins showed that SREBP1a and 1c transcription factors preferentially modulate the manifestation of genes involved in fatty acid synthesis, whereas, SREBP2 primarily regulates the manifestation of genes involved in cholesterol synthesis and transport , . Also, global deletion of both SREBP1a and 1c resulted in embryonic lethality with only 15% survival rate. Interestingly, the surviving mice exhibited a compensatory increase in SREBP2 manifestation . On the other hand, mice with global SREBP2 deletion were not viable with 100% embryonic lethality , . These observations indicated that SREBP2 could compensate for the loss of SREBP1 isoforms, whereas, no compensatory mechanisms could rescue the loss of SREBP2. To understand the physiological and metabolic tasks of SREBP2, earlier studies primarily focused on the liver . While the liver is definitely a key organ for cholesterol and lipid rate of metabolism in the body, the intestinal functions will also be known to be essential for keeping cholesterol homeostasis Orientin . It is, consequently, important to examine the effects of activating SREBP2 specifically in the intestine to determine its effects on the manifestation of intestinal genes and assess the effect of intestinal SREBP2 on body cholesterol homeostasis. In Orientin this regard, treatment with statins, the cholesterol synthesis inhibitors, was recently shown to increase the manifestation of intestinal SREBP2 demonstrating a compensatory mechanism that may reduce their cholesterol decreasing effects . Also, ezetimibe treatment to mice was associated with activation of intestinal SREBP2 . Recent studies provided evidence showing that SREBP2 plays a novel part in many organs including the intestine integrating multiple physiological processes with cholesterol metabolism . For example, SREBP2 has been shown to.