Selective peroxisome proliferator-activated receptor-α modulator K-877 efficiently activates the peroxisome proliferator-activated receptor-α pathway and improves lipid metabolism in mice

Aims/IntroductionPeroxisome proliferator-activated receptor-α (PPARα) is a therapeutic target for hyperlipidemia. K-877 is a new selective PPARα modulator (SPPARMα) that activates PPARα transcriptional activity. The aim of the present study was to assess the effects of K-877 on lipid metabolism in vitro and in vivo compared with those of classical PPARα agonists.Materials and MethodsTo compare the effects of K-877 on PPARα transcriptional activity with those of the classical PPARα agonists Wy14643 (Wy) and fenofibrate (Feno), the cell-based PPARα transactivation luciferase assay was carried out. WT and Ppara−/− mice were fed with a moderate-fat (MF) diet for 6 days, and methionine–choline-deficient (MCD) diet for 4 weeks containing Feno or K-877.ResultsIn luciferase assays, K-877 activated PPARα transcriptional activity more efficiently than the classical PPARα agonists Feno and Wy. After being fed MF diet containing 0.001% K-877 or 0.2% Feno for 6 days, mice in the K-877 group showed significant increases in the expression of Ppara and its target genes, leading to marked reductions in plasma triglyceride levels compared with those observed in Feno-treated animals. These K-877 effects were blunted in Ppara−/− mice, confirming that K-877 activates PPARα. In further experiments, K-877 (0.00025%) and Feno (0.1%) equally improved the pathology of MCD diet-induced non-alcoholic fatty liver disease, with increased expression of hepatic fatty acid oxidation genes.ConclusionsThe present data show that K-877 is an attractive PPARα-modulating drug and can efficiently reduce plasma triglyceride levels, thereby alleviating the dysregulation of lipid metabolism

Data Augmentation for Dysarthric Speech Recognition Based on Text-to-Speech Synthesis

In the field of automatic speech recognition (ASR) for people with dysarthria, it is problematic that not enough training speech data can be collected from people with dysarthria. To solve this problem, we propose a method of data augmentation using text-to-speech (TTS) synthesis. In the proposed data augmentation method, a deep neural network (DNN)-based TTS model is trained by utilizing speech data recorded from a speaker with dysarthria, and the trained TTS model is then used to generate the speaker’s speech data for training the ASR model for the speaker. The results of a speech recognition experiment on a person having spinal muscular atrophy (SMA) showed that the speech recognition error rate was improved by using the proposed data augmentation

Iridium Hydride Mediated Stannane–Fluorine and −Chlorine σ‑Bond Activation: Reversible Switching between X‑Type Stannyl and Z‑Type Stannane Ligands

Iridium­(I) carbonyl hydride Ir­(H)­(CO)­(PPh₃)₃ (<b>1</b>) cleaves the Sn–F and Sn–Cl bonds of four-coordinate stannanes {<i>o</i>-(Ph₂P)­C₆H₄}₃Sn­(X) (X = F (<b>2a</b>) and Cl­(<b>2b</b>)) to afford the stannyl complex [{<i>o</i>-(Ph₂P)­C₆H₄}₃Sn]­Ir­(CO) (<b>3</b>) and HX (X = F and Cl) thanks to phosphine chelation. A plausible intermediate [{<i>o</i>-(Ph₂P)­C₆H₄}₃(Cl)­Sn]­Ir­(H)­(CO) (<b>6</b>) featuring Z-type Ir → R₃SnCl interaction was synthesized by the reaction of <b>3</b> with HCl. Compound <b>6</b> readily regenerated <b>3</b> upon treatment with Brønsted bases, enabling reversible switching between X-type stannyl and Z-type stannane ligands. Density functional theory calculations suggest plausible pathways for Sn–F and Sn–Cl bond cleavage reactions and support the idea that the species bearing a Z-type Ir → R₃SnX interactions (X = F and Cl) are intermediates for Sn–X bond cleavage

Iridium Hydride Mediated Stannane–Fluorine and −Chlorine σ‑Bond Activation: Reversible Switching between X‑Type Stannyl and Z‑Type Stannane Ligands

Iridium­(I) carbonyl hydride Ir­(H)­(CO)­(PPh₃)₃ (<b>1</b>) cleaves the Sn–F and Sn–Cl bonds of four-coordinate stannanes {<i>o</i>-(Ph₂P)­C₆H₄}₃Sn­(X) (X = F (<b>2a</b>) and Cl­(<b>2b</b>)) to afford the stannyl complex [{<i>o</i>-(Ph₂P)­C₆H₄}₃Sn]­Ir­(CO) (<b>3</b>) and HX (X = F and Cl) thanks to phosphine chelation. A plausible intermediate [{<i>o</i>-(Ph₂P)­C₆H₄}₃(Cl)­Sn]­Ir­(H)­(CO) (<b>6</b>) featuring Z-type Ir → R₃SnCl interaction was synthesized by the reaction of <b>3</b> with HCl. Compound <b>6</b> readily regenerated <b>3</b> upon treatment with Brønsted bases, enabling reversible switching between X-type stannyl and Z-type stannane ligands. Density functional theory calculations suggest plausible pathways for Sn–F and Sn–Cl bond cleavage reactions and support the idea that the species bearing a Z-type Ir → R₃SnX interactions (X = F and Cl) are intermediates for Sn–X bond cleavage

Enterohepatic Transcription Factor CREB3L3 Protects Atherosclerosis via SREBP Competitive Inhibition

動脈硬化発症を制御する転写因子の相互作用を発見. 京都大学プレスリリース. 2020-12-09.Background and Aims: cAMP responsive element-binding protein 3 like 3 (CREB3L3) is a membrane-bound transcription factor involved in the maintenance of lipid metabolism in the liver and small intestine. CREB3L3 controls hepatic triglyceride and glucose metabolism by activating plasma fibroblast growth factor 21 (FGF21) and lipoprotein lipase. In this study, we intended to clarify its effect on atherosclerosis. Methods: CREB3L3-deficifient, liver-specific CREB3L3 knockout, intestine-specific CREB3L3 knockout, both liver- and intestine-specific CREB3L3 knockout, and liver CREB3L3 transgenic mice were crossed with LDLR−/− mice. These mice were fed with a Western diet to develop atherosclerosis. Results: CREB3L3 ablation in LDLR−/− mice exacerbated hyperlipidemia with accumulation of remnant APOB-containing lipoprotein. This led to the development of enhanced aortic atheroma formation, the extent of which was additive between liver- and intestine-specific deletion. Conversely, hepatic nuclear CREB3L3 overexpression markedly suppressed atherosclerosis with amelioration of hyperlipidemia. CREB3L3 directly upregulates anti-atherogenic FGF21 and APOA4. In contrast, it antagonizes hepatic sterol regulatory element-binding protein (SREBP)-mediated lipogenic and cholesterogenic genes, and regulates intestinal liver X receptor-regulated genes involved in the transport of cholesterol. CREB3L3 deficiency results in the accumulation of nuclear SREBP proteins. Because both transcriptional factors share the cleavage system for nuclear transactivation, full-length CREB3L3 and SREBPs in the endoplasmic reticulum (ER) functionally inhibit each other. CREB3L3 promotes the formation of the SREBP-insulin induced gene 1 (SREBP-INSIG1) complex to suppress SREBPs for ER-Golgi transport, resulting in ER retention and inhibition of proteolytic activation at the Golgi, and vice versa. Conclusions: CREB3L3 has multi-potent protective effects against atherosclerosis owing to new mechanistic interaction between CREB3L3 and SREBPs under atherogenic conditions