👤 Osamu Ohara

Angiopoietin-like proteins (ANGPTLs) are key regulators of lipid metabolism; however, their response to lipid-lowering therapies remains incompletely understood. The PRESTIGE study compared the effects of pemafibrate add-on versus statin dose doubling on small dense low-density lipoprotein-cholesterol (sdLDL-C) in patients with type 2 diabetes and hypertriglyceridemia receiving statins. This post-hoc analysis investigated changes in circulating ANGPTL levels. Participants were randomized to receive either pemafibrate (0.2 mg/day; n = 48) or double-dose statin therapy (n = 49). Plasma ANGPTL levels and lipid parameters were assessed at baseline and after 12 weeks. ANGPTLs were quantified using specific human ELISA kits. sdLDL-C, LDL-triglycerides (TG), and HDL3-C were measured using the homogeneous assays. Pemafibrate treatment significantly increased circulating ANGPTL3 (+71%) and ANGPTL4 (+143%) levels, with no change in ANGPTL8, whereas statin dose doubling had no effect on ANGPTL levels. Pemafibrate markedly reduced TGs and sdLDL-C, while increasing large buoyant LDL-C, LDL-TG, HDL2,3-C, apolipoprotein AI, and apolipoprotein AII. The increase in ANGPTL3 was not correlated with changes in LDL subspecies but was positively associated with changes in HDL2,3-C. When participants were stratified by baseline ANGPTL3 levels, those in the low ANGPTL3 group showed an increase in LDL-C and LDL-TG in response to pemafibrate. The substantial elevation in ANGPTL4 induced by pemafibrate did not show associations with lipid changes. Pemafibrate markedly elevated circulating ANGPTL3 and ANGPTL4 levels, but these increases were not associated with pro-atherogenic changes in lipoprotein profiles. Notably, baseline ANGPTL3 concentrations may influence the effect of fibrates on LDL-C levels. Show less

Congenital hypogonadotropic hypogonadism (CHH) is a genetically heterogeneous disorder, with multiple causative and candidate genes identified to date. To clarify underlying genetic factors involved in the development of CHH. We examined 88 Japanese patients with CHH using gene panel analysis (GPA) for 14 representative causative genes and whole-exome sequencing (WES) which was initially focused on 41 causative/candidate genes and subsequently expanded to other genes. We extracted rare variants (frequency of <0.01) and performed pathogenic assessment using refined American College of Medical Genetics and Genomics/Association for Molecular Pathology criteria and registered information in ClinVar. Twenty-seven pathogenic/likely pathogenic variants were identified in 30 patients through GPA performed for all 88 patients and in 4 patients through WES performed for 58 patients in whom no obvious disease-causing variants were revealed by GPA. They resided in previously known ANOS1 (6 variants in 7 patients), CHD7 (3 variants in 3 patients), FGFR1 (14 variants in 15 patients), PROKR2 (2 variants in 8 patients), and SOX10 (1 variant in 1 patient), and a hitherto unrecognized ZNF462 (1 variant in 1 patient). One patient had 2 variants. Additionally, potentially CHH-related variants were detected in 12 genes including SEMA4D and CDH2 postulated on the CHH-related molecular network. Furthermore, in the 41 CHH-related genes, the frequency of oligogenicity was significantly higher and the number of rare variants per individual was significantly larger in 54 CHH patients with no discernible pathogenic/likely pathogenic variants than in 100 control individuals. The results support the notion that CHH occurs not only as a monogenic disorder but also as an oligogenic/multifactorial disorder, and suggest the involvement of ZNF462, SEMA4D, and CDH2 variants in the development of CHH. Show less

Being overweight exacerbates various metabolic diseases, necessitating the identification of target molecules for obesity control. In the current study, we investigated common physiological features related to metabolism in mice with low weight gain: (1) G protein-coupled receptor, family C, group 5, member B-knockout; (2) gastric inhibitory polypeptide receptor-knockout; and (3) Iroquois-related homeobox 3-knockout. Moreover, we explored genes involved in metabolism by analyzing differentially expressed genes (DEGs) between low-weight gain mice and the respective wild-type control mice. The common characteristics of the low-weight gain mice were low inguinal white adipose tissue (iWAT) and liver weight despite similar food intake along with lower blood leptin levels and high energy expenditure. The DEGs of iWAT, epididymal (gonadal) WAT, brown adipose tissue, muscle, liver, hypothalamus, and hippocampus common to these low-weight gain mice were designated as candidate genes associated with metabolism. One such gene tetraspanin 7 (Tspan7) from the iWAT was validated using knockout and overexpressing mouse models. Mice with low Tspan7 expression gained more weight, while those with high Tspan7 expression gained less weight, confirming the involvement of the Tspan7 gene in weight regulation. Collectively, these findings suggest that the candidate gene list generated in this study contains potential target molecules for obesity regulation. Further validation and additional data from low-weight gain mice will aid in understanding the molecular mechanisms associated with obesity. Show less

Leukemia inhibitory factor (LIF) receptor, an interleukin 6 cytokine family signal transducer (Il6st, also known as Gp130) that is expressed in the uterine epithelium and stroma, has been recognized to play an essential role in embryo implantation. However, the molecular mechanism underlying Gp130-mediated LIF signaling in the uterine epithelium during embryo implantation has not been elucidated. In this study, we generated mice with uterine epithelium specific deletion of Gp130 (Gp130 ecKO). Gp130 ecKO females were infertile due to the failure of embryo attachment and decidualization. Histomorphological observation revealed that the endometrial shape and embryo position from Gp130 ecKO were comparable to those of the control, and uterine epithelial cell proliferation, whose attenuation is essential for embryo implantation, was controlled in Gp130 ecKO. Comprehensive gene expression analysis using RNA-seq indicates that epithelial Gp130 regulates the expression of estrogen- and progesterone-responsive genes in conjunction with immune response during embryo implantation. We also found that an epithelial remodeling factor, snail family transcriptional repressor 1 (Snai1), was markedly reduced in the pre-implantation uterus from Gp130 ecKO. These results suggest that not only the suppression of uterine epithelial cell proliferation, but also Gp130-mediated epithelial remodeling is required for successful implantation in mice. Show less

Glucose-dependent insulinotropic polypeptide (GIP) has been reported to have an atheroprotective property in animal models. However, the effect of GIP on macrophage foam cell formation, a crucial step of atherosclerosis, remains largely unknown. We investigated the effects of GIP on foam cell formation of, and Show less

Reverse cholesterol transport (RCT) removes excess cholesterol from macrophages to prevent atherosclerosis. ATP-binding cassette, subfamily A, member 1 (ABCA1) is a crucial cholesterol transporter involved in RCT to produce high density lipoprotein-cholesterol (HDLC), and is transcriptionally regulated by liver X receptor alpha (LXRα), a nuclear receptor. Quercetin is a widely distributed flavonoid in edible plants which prevented atherosclerosis in an animal model. We found that quercetin-3-O-glucuronide (Q3GA), a major quercetin metabolite after absorption from the digestive tract, enhanced ABCA1 expression, in vitro, via LXRα in macrophages. In addition, leaf extracts of a traditional Asian edible plant, Nelumbo nucifera (NNE), which contained abundant amounts of quercetin glycosides, significantly elevated plasma HDLC in mice. We are the first to present experimental evidence that Q3GA induced ABCA1 in macrophages, and to provide an alternative explanation to previous studies on arteriosclerosis prevention by quercetin. Show less

BPAG1 (bullous pemphigoid antigen 1) was originally identified as a 230-kDa hemidesmosomal protein and belongs to the plakin family, because it consists of a plakin domain, a coiled-coil rod domain and a COOH-terminal intermediate filament binding domain. To date, alternatively spliced products of BPAG1, BPAG1e, and BPAG1n are known. BPAG1e is expressed in epithelial tissues and localized to hemidesmosomes, on the other hand, BPAG1n is expressed in neural tissues and muscles and has an actin binding domain at the NH(2)-terminal of BPAG1e. BPAG1 is also known as a gene responsible for Dystonia musculorum (dt) neurodegeneration syndrome of the mouse. Another plakin family protein MACF (microtubule actin cross-linking factor) has also an actin binding domain and the plakin domain at the NH(2)-terminal. However, in contrast to its high homology with BPAG1 at the NH(2)-terminal, the COOH-terminal structure of MACF, including a microtubule binding domain, resembles dystrophin rather than plakins. Here, we investigated RNAs and proteins expressed from the BPAG1 locus and suggest novel alternative splicing variants, which include one consisting of the COOH-terminal domain structure homologous to MACF. The results indicate that BPAG1 has three kinds of cytoskeletal binding domains and seems to play an important role in linking the different types of cytoskeletons. Show less