Gene Expression Profiles Induced by a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα) Pemafibrate.

Pemafibrate is the first clinically-available selective peroxisome proliferator-activated receptor α modulator (SPPARMα) that has been shown to effectively improve hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) levels. Global gene expression analysis reveals that the activation of PPARα by pemafibrate induces fatty acid (FA) uptake, binding, and mitochondrial or peroxisomal oxidation as well as ketogenesis in mouse liver. Pemafibrate most profoundly induces HMGCS2 and PDK4, which regulate the rate-limiting step of ketogenesis and glucose oxidation, respectively, compared to other fatty acid metabolic genes in human hepatocytes. This suggests that PPARα plays a crucial role in nutrient flux in the human liver. Additionally, pemafibrate induces clinically favorable genes, such as ABCA1, FGF21, and VLDLR. Furthermore, pemafibrate shows anti-inflammatory effects in vascular endothelial cells. Pemafibrate is predicted to exhibit beneficial effects in patients with atherogenic dyslipidemia and diabetic microvascular complications.

The study on facial soft tissue thickness using Han population in Xinjiang.

Facial profile is an important aspect in physical anthropology, forensic science, and cosmetic research. Thus, facial soft tissue measurement technology plays a significant role in facial restoration. A considerable amount of work has investigated facial soft tissue thickness, which significantly varies according to gender, age, and race. However, only few studies have considered the nutritional status of the investigated individuals. Moreover, no sufficient research among Chinese ethnic groups, particularly Xinjiang population in China, is currently available. Hence, the current study investigated the adaptability of facial soft tissue to the underlying hard tissue among young adults of Han population in Xinjiang, China; the analysis was performed on the basis of gender, skeletal class, and body mass index (BMI). Measurements were obtained from the lateral cephalometric radiographs of 256 adults aged 18-26 years old. Differences in soft tissue thickness were observed between genders and among skeletal classes. With regard to gender, significant differences in soft tissue thickness were found at rhinion, glabella, subnasale, stomion, labrale superius, pogonion, and gnathion among different BMI groups. Thus, nutritional status should be considered when reconstructing an individual's facial profile. Results showed that the thinnest and thickest craniofacial soft tissues existed in rhinion and lip regions, respectively. Overall, this research provides valuable data for forensic facial reconstruction and identification of young adults in Xinjiang, China.

Transcriptome Analysis of K-877 (a Novel Selective PPARα Modulator (SPPARMα))-Regulated Genes in Primary Human Hepatocytes and the Mouse Liver.

AIM: Selective PPARα modulators (SPPARMα) are under development for use as next-generation lipid lowering drugs. In the current study, to predict the pharmacological and toxicological effects of a novel SPPARMα K-877, comprehensive transcriptome analyses of K-877-treated primary human hepatocytes and mouse liver tissue were carried out. METHODS: Total RNA was extracted from the K-877 treated primary human hepatocytes and mouse liver and adopted to the transcriptome analysis. Using a cluster analysis, commonly and species specifically regulated genes were identified. Also, the profile of genes regulated by K-877 and fenofibrate were compared to examine the influence of different SPPARMα on the liver gene expression. RESULTS: Consequently, a cell-based transactivation assay showed that K-877 activates PPARα with much greater potency and selectivity than fenofibric acid, the active metabolite of clinically used fenofibrate. K-877 upregulates the expression of several fatty acid ß-oxidative genes in human hepatocytes and the mouse liver. Almost all genes up- or downregulated by K-877 treatment in the mouse liver were also regulated by fenofibrate treatment. In contrast, the K-877-regulated genes in the mouse liver were not affected by K-877 treatment in the Ppara-null mouse liver. Depending on the species, the peroxisomal biogenesis-related gene expression was robustly induced in the K-877-treated mouse liver, but not human hepatocytes, thus suggesting that the clinical dose of K-877 may not induce peroxisome proliferation or liver toxicity in humans. Notably, K-877 significantly induces the expression of clinically beneficial target genes (VLDLR, FGF21, ABCA1, MBL2, ENPEP) in human hepatocytes. CONCLUSION: These results indicate that changes in the gene expression induced by K-877 treatment are mainly mediated through PPARα activation. K-877 regulates the hepatic gene expression as a SPPARMα and thus may improve dyslipidemia as well as metabolic disorders, such as metabolic syndrome and type 2 diabetes, without untoward side effects.