Our previous genome-wide association study to explore genetic loci associated with lean nonalcoholic fatty liver disease (NAFLD) in Japan suggested four candidate loci, which were mapped to chr6, ...chr7, chr12 and chr13. The present study aimed to identify the locus involved functionally in NAFLD around the association signal observed in chr13. Chromosome conformation capture assay and a database survey suggested the intermolecular interaction among DNA fragments in association signals with the adjacent four coding gene promoters. The four genes were further screened by knockdown (KD) in mice using shRNA delivered by an adeno-associated virus vector (AAV8), and KD of G protein-coupled receptor 180 (Gpr180) showed amelioration of hepatic lipid storage. Gpr180 knockout (KO) mice also showed ameliorated hepatic and plasma lipid levels without influencing glucose metabolism after high-fat diet intake. Transcriptome analyses showed downregulation of mTORC1 signaling and cholesterol homeostasis, which was confirmed by weakened phosphorylation of mTOR and decreased activated SREBP1 in Gpr180KO mice and a human hepatoma cell line (Huh7). AAV8-mediated hepatic rescue of GPR180 expression in KO mice showed recovery of plasma and hepatic lipid levels. In conclusion, ablation of GPR180 ameliorated plasma and hepatic lipid levels, which was mediated by downregulation of mTORC1 signaling.
•HLA‐DPB1*19:01, rs878860 C, and the rs17822931 C allele decreased the relative abundance of Corynebacterium.•HLA‐DPB1*09:01, *14:01, *19:01, rs878860 C, rs10791824 G , and the rs17822931 C allele ...increased that of Staphylococcus.•HLA‐DPB1*04:01, *05:01, and the rs17822931 C allele increased the axillary E3M2H intensity.
The distinct diversity of the human skin microbiome depends not only on the body site but also the individual. Host-commensal interactions have been described for the gut microbiome, but little is known about the epidermal microbiome.
The present study investigated whether genetic variants associated with skin traits affect the axillary microbiome.
Eight skin trait-related single nucleotide polymorphisms and HLA-A, -B, -C, and –DPB1 were genotyped in 186 Japanese males. From axillary swabs, the intensity of a representative axillary odor, trans (E) isomer of 3-methyl-2-hexenoic acid (E3M2H), was quantified with gas chromatography-tandem mass spectrometry analysis, the diversity of the axillary microbiome was evaluated with a 16 s rRNA metagenomic approach, and the association of these characteristics was assessed statistically.
A risk allele for atopic dermatitis of rs878860 in NLRP10 and the allele for wet earwax of rs17822931 in ABCC11 decreased the relative abundance of Corynebacterium. Conversely, these alleles increased the relative abundance of Staphylococcus. Metagenomic analysis revealed that β-diversity showed significant dissimilarity at the weighted Unifrac distance between minor allele carrier and non-carrier groups in HLA‐DPB1*05:01, rs17822931, and rs878860. HLA‐DPB1*04:01, HLA‐DPB1*05:01, and rs17822931 were associated with E3M2H.
We identified novel candidate loci associated with the axillary microbiome and malodor.
The present study aimed to investigate the transcriptional regulation of Kbtbd11 in adipose tissue. To elucidate the physiological role of Kbtbd11 gene expression, adipose Kbtbd11 mRNA expression ...levels were estimated under various feeding states in wild-type mice. Kbtbd11 expression increased in a time-dependent manner in the adipose tissue in mice fed on chow diet, whereas the promotion of Kbtbd11 mRNA expression by refeeding was attenuated in mice fed on high-fat (HF) diet, suggesting the suppression of Kbtbd11 mRNA expression under HF diets and that changes in mRNA levels were associated with regulation of the transcription activity of Kbtbd11 by some transcription factors. To investigate the transcriptional regulation of Kbtbd11, the fragment upstream of either mouse Kbtbd11 or human KBTBD11 promoter was inserted into a luciferase vector. Luciferase reporter assays revealed that both mouse and human KBTBD11 promoter activity was increased by USF1. Direct USF1 binding to the Ebox in the Kbtbd11 promoter was confirmed by electrophoretic mobility shift and chromatin immunoprecipitation assays. In addition, the adipocyte differentiation marker levels increased instantly in Kbtbd11-overexpressing Usf1 knockdown cells than in Usf1 knockdown cells. These results imply an association of between Kbtbd11 with Usf1 expression and suggest the involvement of Kbtbd11 in a novel adipogenesis pathway.
Cell biology; Cell Differentiation; Gene Expression; Gene Regulation; Transcription Factor; Biochemistry; Molecular Biology; Obesity; Kbtbd11; 3T3-L1 differentiation; USF1; transcriptional regulation.
N4BP2l1, which is highly expressed in oral squamous cell carcinoma, is associated with poor prognosis. However, N4bp2l1's role in adipogenesis remains unknown. We aimed to clarify the expression ...profile and transcriptional regulation of N4bp2l1 to elucidate the functions underlying the role of N4bp2l1 in adipocyte differentiation. Our results revealed that N4bp2l1 mRNA expression increased in 3T3-L1 cells in a differentiation-dependent manner. To investigate the transcriptional regulation of N4bp2l1, the 2-kb 5′ region upstream of the mouse N4bp2l1 promoter was cloned into a luciferase vector. Luciferase reporter assays indicated that USF1 induces the N4bp2l1 promoter activity. Electrophoretic mobility shift and chromatin immunoprecipitation assays confirmed that USF1 directly binds to the Ebox in the N4bp2l1 promoter. Furthermore, the expressions of adipocyte differentiation markers significantly decreased in N4bp2l1-knockdown cells compared with those in control cells. Our results demonstrated that N4bp2l1 is a novel USF1 target gene that may be involved in adipogenesis regulation.
•N4bp2l1 expression is increased in a differentiation-dependent manner in 3T3-L1.•N4bp2l1 is a novel USF1 target gene.•USF1 directly binds to the Ebox in the N4bp2l1 promoter.•Inhibition of 3T3-L1 adipocyte differentiation by N4bp2l1 knockdown.
This study aimed to examine the effect of the HMGB1 peptide on Bronchopulmonary dysplasia (BPD)-related lung injury in a mouse model.
HMGB1 peptide ameliorates lung injury by suppressing the release ...of inflammatory cytokines and decreasing soluble collagen levels in the lungs. Single-cell RNA sequencing showed that the peptide suppressed the hyperoxia-induced inflammatory signature in macrophages and the fibrotic signature in fibroblasts. These changes in the transcriptome were confirmed using protein assays.
Systemic administration of HMGB1 peptide exerts anti-inflammatory and anti-fibrotic effects in a mouse model of BPD. This study provides a foundation for the development of new and effective therapies for BPD.
•Bronchopulmonary dysplasia (BPD) is a chronic lung disorder.•HMGB1 peptide exerts anti-inflammatory and anti-fibrotic effects.•HMGB1 peptide may be used clinically in the treatment of BPD in the future.
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