Language：English   Publishing type：Research paper (scientific journal)  

Microglia are brain specific macrophages and the only immune cells in the brain. Microglia sense the systemic immune status and contribute to neurological and psychiatric disorders. We previously showed that systemic immune activation induces microglial migration on vessels that regulate the blood brain barrier permeability. In this study, using Toll like receptor 7 induced systemic lupus erythematosus model mice, we found microglia migration on vessels and significant T cell infiltration in the brain. Additionally, microglia interacting with T cell expressed MHC class II molecules in some cases, suggesting the antigen presentation of microglia in systemic lupus erythematosus model mice. This research provides insights on the autoimmune antibody expression in the brain.

DOI： 10.18999/nagjms.87.3.509

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Language：English   Publishing type：Research paper (scientific journal)  

As obesity progresses, dynamic tissue remodeling of adipose tissue occurs over time, that is, adipocyte hypertrophy, chronic inflammation, and interstitial fibrosis. Some obese individuals exhibit healthy adipose tissue expansion, characterized by modest inflammation and fibrosis despite adipocyte hypertrophy, resulting in "Metabolically Healthy Obesity (MHO)". In this study, we investigated the effects of transient weight loss on adipose tissue remodeling during the development of obesity. Male C57BL6/J mice received various types of transient weight loss treatments during diet-induced obesity. A 2-week weight loss intervention during the inflammatory phase promoted healthy adipose tissue expansion, reduced ectopic lipid accumulation, and improved glucose metabolism. In contrast, protocols with shorter duration and delayed intervention, failed to induce MHO. Since serum concentrations of ketone bodies were elevated during weight loss, we examined the effects of hyperketonemia on obesity-induced adipose tissue remodeling. Transient treatment with 1,3-butanediol (BD), which increased serum ketone body concentrations to levels similar to those observed during weight loss, induced healthy adipose tissue expansion and reduced hepatic steatosis even during continuous high-fat diet (HFD) feeding. Ketone bodies effectively suppressed activation of adipose tissue fibroblasts in vivo and in vitro. This study provides evidence that an appropriate dietary intervention can promote healthy adipose tissue expansion in mice, even after the regaining of weight, thereby leading to MHO. As the underlying mechanism, our data revealed a key role for ketone bodies in suppressing activation of adipose tissue fibroblasts. This study paves the way for nutritional approaches to induce MHO.

DOI： 10.1096/fj.202501121R

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Language：English   Publishing type：Research paper (scientific journal)  

Recent evidence has shown that adipose tissue eventually develops fibrosis through complex cellular crosstalk. Although advances in single-cell transcriptomics have provided new insights into cell diversity during this process, little is known about the interactions among the distinct cell types. In this study, we employed single-cell analytical approaches to investigate cell-tocell communications between macrophages and fibroblasts in the adipose tissue of diet-induced obese mice. Spatial transcriptomics was used to understand local cellular interaction within crown-like structures (CLSs), a characteristic histological feature of adipose tissue in obesity driving inflammation and fibrosis. Macrophages and fibroblasts were divided into several subclusters that appeared to interact more intensely and complexly with the degree of obesity. Besides previously reported Lipid-associated macrophages (LAMs), we found a small subcluster expressing Macrophage-inducible C-type lectin (Mincle), specifically localizing to CLSs. Mincle signaling increased the expression of Oncostatin M (Osm), suppressing collagen gene expression in adipose tissue fibroblasts. Consistent with these findings, Osm-deficiency in immune cells enhanced obesity-induced adipose tissue fibrosis in vivo. Moreover, Osm expression was positively correlated with Mincle expression in human adipose tissue during obesity. Our results suggest that Osm secreted by Mincle-expressing macrophages is involved in dynamic adipose tissue remodeling in the proximity of CLSs.

DOI： 10.2337/db24-0762

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Language：English   Publishing type：Research paper (scientific journal)  

Accumulation of lipotoxic lipids, such as free cholesterol, induces hepatocyte death and subsequent inflammation and fibrosis in the pathogenesis of nonalcoholic steatohepatitis (NASH). However, the underlying mechanisms remain unclear. We have previously reported that hepatocyte death locally induces phenotypic changes in the macrophages surrounding the corpse and remnant lipids, thereby promoting liver fibrosis in a murine model of NASH. Here, we demonstrated that lysosomal cholesterol overload triggers lysosomal dysfunction and profibrotic activation of macrophages during the development of NASH. β-cyclodextrin polyrotaxane (βCD-PRX), a unique supramolecule, is designed to elicit free cholesterol from lysosomes. Treatment with βCD-PRX ameliorated cholesterol accumulation and profibrotic activation of macrophages surrounding dead hepatocytes with cholesterol crystals, thereby suppressing liver fibrosis in a NASH model, without affecting the hepatic cholesterol levels. In vitro experiments revealed that cholesterol-induced lysosomal stress triggered profibrotic activation in macrophages predisposed to the steatotic microenvironment. This study provides evidence that dysregulated cholesterol metabolism in macrophages would be a novel mechanism of NASH.

DOI： 10.1084/jem.20220681

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Language：English   Publishing type：Research paper (scientific journal)  

The molecular pathogenesis of nonalcoholic steatohepatitis (NASH) includes a complex interaction of metabolic stress and inflammatory stimuli. Considering the therapeutic goals of NASH, it is important to determine whether the treatment can prevent the progression from NASH to hepatocellular carcinoma. Taxifolin, also known as dihydroquercetin, is a natural bioactive flavonoid with antioxidant and anti-inflammatory properties commonly found in various foods and health supplement products. In this study, we demonstrated that Taxifolin treatment markedly prevented the development of hepatic steatosis, chronic inflammation, and liver fibrosis in a murine model of NASH. Its mechanisms include a direct action on hepatocytes to inhibit lipid accumulation. Taxifolin also increased brown adipose tissue activity and suppressed body weight gain through at least two distinct pathways: direct action on brown adipocytes and indirect action via fibroblast growth factor 21 production in the liver. Notably, the Taxifolin treatment after NASH development could effectively prevent the development of liver tumors. Collectively, this study provides evidence that Taxifolin shows pleiotropic effects for the treatment of the NASH continuum. Our data also provide insight into the novel mechanisms of action of Taxifolin, which has been widely used as a health supplement with high safety.

DOI： 10.3390/nu15020350

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Diabetes and obesity contribute to the pathogenesis of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). However, how diabetes and obesity accelerate liver tumorigenesis remains to be fully understood. Moreover, to verify the therapeutic potential of anti-diabetic drugs, there exists a strong need for appropriate animal models that recapitulate human pathophysiology of NASH and HCC. METHODS: We established a novel murine model of NASH-associated liver tumors using genetically obese melanocortin 4 receptor-deficient mice fed on Western diet in combination with a chemical procarcinogen, and verified the validity of our model in evaluating drug efficacy. FINDINGS: Our model developed multiple liver tumors together with obesity, diabetes, and NASH within a relatively short period (approximately 3 months). In this model, sodium glucose cotransporter 2 inhibitor Tofogliflozin prevented the development of NASH-like liver phenotypes and the progression of liver tumors. Tofogliflozin attenuated p21 expression of hepatocytes in non-tumorous lesions in the liver. INTERPRETATION: Tofogliflozin treatment attenuates cellular senescence of hepatocytes under obese and diabetic conditions. This study provides a unique animal model of NASH-associated liver tumors, which is applicable for assessing drug efficacy to prevent or treat NASH-associated HCC.

DOI： 10.1016/j.biopha.2021.111738

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Language：Japanese   Publisher：(一社)日本内分泌学会  

Language：English   Publishing type：Research paper (scientific journal)  

Although recent evidence suggests the involvement of iron accumulation in the pathogenesis of nonalcoholic steatohepatitis (NASH), the underlying mechanisms remain poorly understood. Previously, we reported a unique histological structure termed "crown-like structure (CLS)," where liver-resident macrophages (Kupffer cells) surround dead hepatocytes, scavenge their debris, and induce inflammation and fibrosis in NASH. In this study, using magnetic column separation, we show that iron-rich Kupffer cells exhibit proinflammatory and profibrotic phenotypic changes during the development of NASH, at least partly, through activation of MiT/TFE transcription factors. Activation of MiT/TFE transcription factors is observed in Kupffer cells forming CLSs in murine and human NASH. Iron chelation effectively attenuates liver fibrosis in a murine NASH model. This study provides insight into the pathophysiologic role of iron in NASH. Our data also shed light on a unique macrophage subset rich in iron that contributes to CLS formation and serves as a driver of liver fibrosis.

DOI： 10.1016/j.isci.2020.102032

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Language：English   Publishing type：Research paper (scientific journal)  

Accumulating evidence indicates that cell death triggers sterile inflammation and that impaired clearance of dead cells causes nonresolving inflammation; however, the underlying mechanisms are still unclear. Here, we show that macrophage-inducible C-type lectin (Mincle) senses renal tubular cell death to induce sustained inflammation after acute kidney injury in mice. Mincle-deficient mice were protected against tissue damage and subsequent atrophy of the kidney after ischemia-reperfusion injury. Using lipophilic extract from the injured kidney, we identified β-glucosylceramide as an endogenous Mincle ligand. Notably, free cholesterol markedly enhanced the agonistic effect of β-glucosylceramide on Mincle. Moreover, β-glucosylceramide and free cholesterol accumulated in dead renal tubules in proximity to Mincle-expressing macrophages, where Mincle was supposed to inhibit clearance of dead cells and increase proinflammatory cytokine production. This study demonstrates that β-glucosylceramide in combination with free cholesterol acts on Mincle as an endogenous ligand to induce cell death-triggered, sustained inflammation after acute kidney injury.

DOI： 10.1084/jem.20192230

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Language：Japanese   Publisher：(一社)日本認知症学会  

Language：English   Publishing type：Research paper (scientific journal)  

Nonalcoholic steatohepatitis (NASH) is a hepatic phenotype of the metabolic syndrome, and increases the risk of cirrhosis and hepatocellular carcinoma (HCC). Although increasing evidence points to the therapeutic implications of certain types of anti-diabetic agents in NASH, it remains to be elucidated whether their effects on NASH are independent of their effects on diabetes. Genetically obese melanocortin 4 receptor-deficient (MC4R-KO) mice fed Western diet are a murine model that sequentially develops hepatic steatosis, NASH, and HCC in the presence of obesity and insulin resistance. In this study, we investigated the effect of the dipeptidyl peptidase-4 (DPP-4) inhibitor anagliptin on NASH and HCC development in MC4R-KO mice. Anagliptin treatment effectively prevented inflammation, fibrosis, and carcinogenesis in the liver of MC4R-KO mice. Interestingly, anagliptin only marginally affected body weight, systemic glucose and lipid metabolism, and hepatic steatosis. Histological data and gene expression analysis suggest that anagliptin treatment targets macrophage activation in the liver during the progression from simple steatosis to NASH. As a molecular mechanism underlying anagliptin action, we showed that glucagon-like peptide-1 suppressed proinflammatory and profibrotic phenotypes of macrophages in vitro. This study highlights the glucose metabolism-independent effects of anagliptin on NASH and HCC development.

DOI： 10.1038/s41598-020-57935-6

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/nm.4479

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Total pages：5   Language：Japanese

Total pages：7  

CiNii Research

Total pages：5  

CiNii Research

Total pages：5  

CiNii Research

Language：Japanese

Total pages：5  

CiNii Research

Authorship：Lead author  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)  

Event date： 2025.7

Venue：筑波  

Event date： 2025.3

Venue：東京  

Event date： 2024.11

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Venue：横浜   Country：Japan  

Event date： 2024.6

Presentation type：Oral presentation (invited, special)  

Event date： 2024.1

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Event date： 2023.6

Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

Event date： 2023.6

Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

Event date： 2023.3

Language：English   Presentation type：Symposium, workshop panel (public)  

Event date： 2022.11

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Event date： 2022.11

Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

Event date： 2022.7

Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

Venue：福岡（久留米シティプラザ）  

Event date： 2025.10

Language：Japanese  

Venue：岡山  

Event date： 2024.12

Language：English   Presentation type：Poster presentation  

Country：Japan  

Event date： 2024.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：横浜   Country：Japan  

Event date： 2024.3

Language：English   Presentation type：Poster presentation  

Venue：Killarney, Ireland   Country：Ireland  

Event date： 2023.9

Language：English  

Venue：熊本   Country：Japan  

Event date： 2023.6

Language：Japanese   Presentation type：Oral presentation (general)  

Event date： 2023.6

Language：English   Presentation type：Oral presentation (general)  

Event date： 2023.2

Language：Japanese   Presentation type：Oral presentation (general)  

Event date： 2023.1

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Venue：徳島（徳島大学病院）  

Event date： 2022.7

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Event date： 2022.6

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京  

Event date： 2022.6

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：兵庫  

Event date： 2022.6

Language：Japanese   Presentation type：Oral presentation (general)  

Event date： 2021.12

Language：English  

Event date： 2021.12

Event date： 2021.7

Language：Japanese  

Event date： 2021.4

Language：Japanese  

Event date： 2020.5

Event date： 2020.5

Language：Japanese  

Event date： 2019.12

Event date： 2018.12

Language：English   Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2018.11

Language：English   Presentation type：Oral presentation (invited, special)  

Venue：Gunma   Country：Japan  

Event date： 2018.8

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Country：Japan  

Event date： 2018.6

Language：English   Presentation type：Poster presentation  

Venue：Basel   Country：Switzerland  

Event date： 2018.4

Language：Japanese   Presentation type：Oral presentation (general)  

Event date： 2018.4

Presentation type：Oral presentation (invited, special)  

Venue：東京