characterized by two repeats of the codon CAC separated by two intervening C nucleotides (5’-CACCCCAC-3’). The sterol regulatory element-binding protein-1 (SREBP-1), a transcription factor, targets the CAC repeats of SRE-1 to regulate the protein’s transcription. However, the VLDLR gene is encoded by two SRE-1-like sequences that contain single nucleotide polymorphisms. These polymorphisms disrupt the SREBP-1 binding to the CAC repeats, and hence eliminate the feedback mechanism seen in other proteins. VLDLR expression is regulated by peroxisome proliferator-activated receptor-gamma (PPAR-γ). A 2010 study showed that the prescription drug Pioglitazone, an agonist of PPAR-γ, increases VLDLR mRNA expression and protein levels in experiments using mouse fibroblasts. The Pioglitazone treated mice exhibited a higher conversion rate of plasma triglycerides into epididymal fats. As expected, mice deficient in VLDLR did not show this same response. These results suggest that VLDLR is important in fat accumulation. Many other hormones and dietary factors also regulate VLDLR expression. Thyroid hormone positively regulates VLDLR expression in skeletal muscles of rats, but not in adipose or heart tissues. In rabbits, VLDLR expression in heart muscle is up-regulated by estrogen and down-regulated by granulocyte-macrophage colony-stimulating factor. In trophoblast-derived cell lines, up-regulated VLDLR expression occurs when cells are incubated with hypolipidemic agents such as insulin and clofibrate. In contrast, 8-bromoadenosine 3',5'-cyclic monophosphate (8-bromo-cAMP) down-regulates VLDLR expression. Finally, VLDLR is affected by the presence of apoE and LDLR. The presence of apoE is required for VLDLR expression regulation, while the absence of LDLR alters the sterol-regulatory-element-1-like sequences of VLDLR to make them functional in only heart and skeletal muscle. Function Beyond the nervous system VLDLR is a peripheral lipoprotein receptor that functions in lipoprotein metabolism, cardiac fatty acid metabolism, and fat deposition. In effect, VLDLR will allow cholesterol to reach tissues from the bloodstream, where it may be used in cellular membranes. In addition, it will allow fatty acids to get into cells where they may be used as an energy source. Overall, VLDLR primarily modulates the extra-hepatic metabolism of triglyceride-rich lipoproteins. Lipoprotein uptake VLDLR only plays a discrete role in lipid metabolism, but is more significant in stressed situations. Mice with double knockouts in VLDLR and LDLR have higher serum triglyceride levels than those with only a knockout in the LDLR gene. In addition, LDLR knockout mice overexpressing VLDLR have decreased serum triglyceride levels. Although fat deposition is close to normal without VLDLR, its role gains importance when LDLR is deficient.