Scope: Palmitoleic acid (palmitoleate; C16:1 n-7), an omega-7 monounsaturated fatty acid (MUFA) found in plants and marine sources, has been shown to favorably modulate lipid and glucose metabolism. However, its impact on atherosclerosis has not been examined in detail. Methods and Results: LDL receptor knock out (LDLR-KO) mice are fed a Western diet supplemented with 5% (w/w) palmitoleate concentrate, oleic-rich olive oil, or none (control) for 12 weeks. Dietary palmitoleate increases hepatic C16:1 levels, improves plasma and hepatic lipid/lipoprotein profiles (40% decrease in triglycerides), and reduces the atherosclerotic plaque area by 45% compared with control or olive oil group (p < 0.05). These favorable changes are accompanied by the downregulation of key genes, such as Srebp1c, Scd1, Il-1β, and Tnfα. ApoB-depleted plasma from mice fed palmitoleate has increased cholesterol efflux capacity by 20% from ABCA1-expressing cells (p < 0.05). A beneficial effect of palmitoleate on glucose metabolism (54% decreased in HOMA-IR, p < 0.05) is also observed. Conclusions: Dietary-supplemented palmitoleate reduces atherosclerosis development in LDLR-KO mice, and is associated with improvement of lipid and glucose metabolism and favorable changes in regulatory genes involved in lipogenesis and inflammation. These findings imply the potential role of dietary palmitoleate in the prevention of cardiovascular disease and diet-induced metabolic disorders.

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The Ewing sarcoma family of tumors (ESFT) are high-grade small round blue cell malignancies traditionally presenting in children and adolescents. The most common site of primary disease is bone, though extraskeletal primary sites are well-recognized. 1 We present six cases of primary ESFT of the kidney and one case of the adrenal gland. Patients were 11-18 years of age at diagnosis. Metastases at diagnosis were present in most cases (n=6). All patients underwent surgery, and most received radiation (n=5). Five patients relapsed after initial remission.Comprehensive review of the primary renal ESFT literature was used to analyze various factors, including age, gender, disease metrics, metastases at diagnoses, and overall survival in a total of 362 cases. Notably, while the general ESFT population has reported rates of metastasis at diagnosis of 20-25%, 2 this rate in the renal ESFT population was 53% with a rate of 59% in adolescent and young-adult (AYA) patients (11-24 years). Nodal disease at diagnosis was present in 24% of renal ESFT cases compared with 3.2% in patients with primary skeletal ESFT. 3 While this malignant process may share histologic and molecular features with its bone and soft tissue counterparts, primary renal ESFT presentations appear to be more aggressive and have worse outcomes.

Introduction: HMG-CoA reductase is a membrane protein of the endoplasmic reticulum that catalyzes reduction of HMG-CoA to mevalonate, a rate-limiting step in the synthesis of cholesterol and nonsterol isoprenoids, which exert feedback control on HMGCR through multiple mechanisms. These mechanisms ensure constant synthesis of essential nonsterol isoprenoids, while avoiding toxic cholesterol accumulation. One mechanism involves sterol-induced ubiquitination of HMGCR, marking the enzyme for degradation from ER membranes, a process augmented by nonsterol isoprenoids. We examine the contribution of sterol-accelerated ubiquitination/degradation to overall regulation of HMGCR in livers of mice. Methods: Forty mice, including 20 wild-type (WT) and 20 knock-in (Ki) mice expressing ubiquitination-resistant HMGCR, were fed diets containing only chow, or chow supplemented with 0.1, 0.3, or 1% cholesterol. After five days of feeding, livers were harvested for measurements of cholesterol and triglycerides, immunoblot analysis, and qRT-PCR of genes related to cholesterol, nonsterol isoprenoid, and fatty acid synthesis. Results: Normalization of mRNA to protein levels indicates that HMGCR Ki livers contain a more HMGCR protein despite mRNA downregulation. Protein and gene expression of SREBP2 and its target genes, which contribute to cholesterol synthesis, decreased as expected with increased dietary cholesterol. Conversely, protein and gene expression of SREBP1 and its target genes increased, likely due to SREBP1c predominance toward fatty acid synthesis, which prevents cholesterol accumulation. Conclusion: The increase in HMGCR protein relative to mRNA suggests that significant post-transcriptional regulation exists in the form of impaired degradation. Furthermore, these normalized values indicate that accumulation of protein is primarily due to impaired degradation at lower cholesterol levels (chow, 0.1%); however, at high cholesterol levels (0.3, 1%), a greater degree of transcriptional control from sterol-mediated inhibition of SREBP2 regulates HMGCR due to negative feedback. This study demonstrates the role of degradative control on inhibition of HMGCR and may assist in reducing HMGCR accumulation during statin therapy.