イソラムネチンおよびその類縁化合物による非アルコール性脂肪性肝炎に対する緩和効果

この博士論文は内容の要約のみの公開（または一部非公開）になっています筑波大学 (University of Tsukuba)201

イソラムネチンおよびその類縁化合物による非アルコール性脂肪性肝炎に対する緩和効果

筑波大学University of Tsukuba博士（医科学）Doctor of Philosophy in Medical Science2019【要旨】thesi

Isorhamnetin Alleviates Steatosis and Fibrosis in Mice with Nonalcoholic Steatohepatitis

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Deciphering liver fibrosis with next generation omics

Ph. D. Thesis.Fibrotic diseases underpin around 45% of all chronic diseases and deaths in the western world. In particular, chronic liver diseases represent a major threat to the public health affecting around 1.5 billion people in the world and accounting for 2 million deaths annually. Hepatic fibrosis is a progressive pathology characterized by a dysregulation of the woundhealing response, resulting in extracellular matrix (ECM) accumulation. Hepatic Stellate cells (HCSs) are the major contributor to ECM deposition in liver diseases. Thus, HSCs are crucial for liver fibrosis progression. Understanding molecular mechanisms of HSC activation is therefore of major interest in study of liver fibrosis. To this end, miRNA sequencing during HCSs activation time-course was employed, which showed significant differences in miRNA expression which may be important for fibrosis progression. 2D cultures are widely used in the study of liver disease. However, they do present limitations, which can be overcome by the use of Bioreactor-cultured Precision cut liver slices (PCLSs) technology developed in our lab. Using this technology, human PCLSs were created and RNA sequencing, proteome and secretome analysis performed. In this thesis, I showed that fibrotic PCLSs present differential gene/protein expression patterns that could be associated with the fibrotic outcome. Previous studies in our lab reported an epigenetic mechanism that generated heritable adaptation in wound healing response in male rats. The adapted rats showed significant fibrogenesis/fibrosis reduction. I was interested in studying the mechanism behind the adaptation. Using omics techniques, I analysed gene expression pattern in adapted livers and differences in DNA methylome and proteome in sperm, as potential mechanism for adaptation transmission. Moreover, I studied the potential of adaptive inheritance transmission via female lineage. This study provides evidence of i) the importance of miRNA during HSCs activation, ii) differential gene/protein expression patterns associated with the fibrotic outcome in human liver, iii) differential gene expression in adapted livers and epigenetic modifications in sperm as a putative mechanism of the adaptive response transmission. This adaptive response was absent in female offspring, suggesting only males can transmit the adaptation.Dr Lorna Jones Legacy gif

PPARs as Key Mediators of Metabolic and Inflammatory Regulation

Mounting evidence suggests a bidirectional relationship between metabolism and inflammation. Molecular crosstalk between these processes occurs at different levels with the participation of nuclear receptors, including peroxisome proliferator-activated receptors (PPARs). There are three PPAR isotypes, α, β/δ, and γ, which modulate metabolic and inflammatory pathways, making them key for the control of cellular, organ, and systemic processes. PPAR activity is governed by fatty acids and fatty acid derivatives, and by drugs used in clinics (glitazones and fibrates). The study of PPAR action, also modulated by post-translational modifications, has enabled extraordinary advances in the understanding of the multifaceted roles of these receptors in metabolism, energy homeostasis, and inflammation both in health and disease. This Special Issue of IJMS includes a broad range of basic and translational article, both original research and reviews, focused on the latest developments in the regulation of metabolic and/or inflammatory processes by PPARs in all organs and the microbiomes of different vertebrate species

The role of 3’,4’-dihydroxyphenyl-γ-valerolactone, the gut microbiota metabolite of (−)-epicatechin, in reducing insulin resistance

Background: Hydroxyphenyl-γ-valerolactones (HPVLs) are microbiota-derived metabolites of monomeric catechins and comprise about 33 % of total human catechin metabolites. HPVLs could therefore contribute to the previously reported beneficial effects of (−)-epicatechin (EC) on high-fat (HF) diet induced weight gain and insulin resistance (IR) in mice. Aims: Assess the bioavailability and metabolism of 3’,4’-dihydroxyphenyl-γ-valerolactone (34DHPVL) and determine its effects on IR, body weight gain, steatosis and hepatic gene expression changes when fed directly to mice on HF or low-fat (LF) diets. Methods: Male C57BL/6J mice were fed LF (10 % kcal) or HF (60 % kcal) diets with or without 20 mg/kg body weight (BW) supplementation of EC or 34DHPVL for 15-weeks. A fasted glucose tolerance test was performed at week-13 to assess IR. Plasma and liver lipids were quantified, and the effects on global gene expression assessed via RNA-sequencing analysis of liver tissue. Results: Gavaged 34DHPVL was highly bioavailable and present in plasma solely as sulfated and glucuronidated conjugates. 34DHPVL dietary supplementation reduced plasma glucose A.U.C (p-= 0.12) albeit non-significantly (ns), paradoxically increased plasma insulin (p-<-0.01) and liver lipids (ns) but had no effect on HF diet-induced BW gain. EC dietary supplementation improved insulin sensitivity (HOMA-IR, p-=-0.07), and mitigated HF diet-induced BW and liver weight gain and hepatic lipid accumulation (all p-<-0.05). Both EC and 34DHPVL protected against HF diet-induced increases in expression of genes involved in glucose production and increased expression of insulin signalling genes, but the effects of EC were much stronger. Conclusion: These data suggest that 34DHPVL may contribute modestly to the beneficial effects of EC consumption on HF-diet induced IR, but it is clear that the effects of the parent EC are stronger. 34DHPVL is not responsible for the mitigation of HF diet-induced BW gain caused by EC, which suggests that this effect is caused by EC conjugates