Medium-chain fatty acids suppress lipotoxicity-induced hepatic fibrosis via the immunomodulating receptor GPR84

食事性肥満から肝炎発症に関わる制御因子の同定 --中鎖脂肪酸油による予防・GPR84標的NASH治療薬の可能性--. 京都大学プレスリリース. 2023-01-18.Medium-chain triglycerides (MCTs), which consist of medium-chain fatty acids (MCFAs), are unique forms of dietary fat with various health benefits. G protein–coupled 84 (GPR84) acts as a receptor for MCFAs (especially C10:0 and C12:0); however, GPR84 is still considered an orphan receptor, and the nutritional signaling of endogenous and dietary MCFAs via GPR84 remains unclear. Here, we showed that endogenous MCFA-mediated GPR84 signaling protected hepatic functions from diet-induced lipotoxicity. Under high-fat diet (HFD) conditions, GPR84-deficient mice exhibited nonalcoholic steatohepatitis (NASH) and the progression of hepatic fibrosis but not steatosis. With markedly increased hepatic MCFA levels under HFD, GPR84 suppressed lipotoxicity-induced macrophage overactivation. Thus, GPR84 is an immunomodulating receptor that suppresses excessive dietary fat intake–induced toxicity by sensing increases in MCFAs. Additionally, administering MCTs, MCFAs (C10:0 or C12:0, but not C8:0), or GPR84 agonists effectively improved NASH in mouse models. Therefore, exogenous GPR84 stimulation is a potential strategy for treating NASH

Financial Transmission Mechanism between Financial Centers and Peripheries

The  causes  of  contagion  effects  during  periods  of  crisis  are  still  unable  to  be  fully explained  by  fundamental  factors.  This  paper  focuses  on  non-fundamental  explanatory factors  such  as  inancial  centers'  shock  ampliication  effects  induced  by  global  portfolio investors  and  extends  Kaminsky  and  Reinhart  (2003)'s  center-periphery  framework  by introducing three time zones for the analysis of conditional distribution of 37 countries' daily stock returns from 1994 to 2003, and accessibility of stock markets to investigate if inancial centers stabilize or amplify shocks. Centers such as U.S. and Germany played a vital role in propagating turmoil in G7 countries and spreading shocks to countries in other regions during periods of crisis, whereas Japan ampliied turmoil in Asian peripheries only within the same region. In contrast, an emerging center, Hong Kong, appears to have much stronger shock-ampliication effects on developing countries than the three centers.  activate javascrip

Financial Transmission Mechanism between Financial Centers and Peripheries

The &nbsp;causes &nbsp;of &nbsp;contagion &nbsp;effects &nbsp;during &nbsp;periods &nbsp;of &nbsp;crisis &nbsp;are &nbsp;still &nbsp;unable &nbsp;to &nbsp;be &nbsp;fully&nbsp;explained &nbsp;by &nbsp;fundamental &nbsp;factors. &nbsp;This &nbsp;paper &nbsp;focuses &nbsp;on &nbsp;non-fundamental &nbsp;explanatory&nbsp;factors &nbsp;such &nbsp;as &nbsp;inancial &nbsp;centers' &nbsp;shock &nbsp;ampliication &nbsp;effects &nbsp;induced &nbsp;by &nbsp;global &nbsp;portfolio&nbsp;investors &nbsp;and &nbsp;extends &nbsp;Kaminsky &nbsp;and &nbsp;Reinhart &nbsp;(2003)'s &nbsp;center-periphery &nbsp;framework &nbsp;by&nbsp;introducing three time zones for the analysis of conditional distribution of 37 countries' daily&nbsp;stock returns from 1994 to 2003, and accessibility of stock markets to investigate if inancial&nbsp;centers stabilize or amplify shocks. Centers such as U.S. and Germany played a vital role&nbsp;in propagating turmoil in G7 countries and spreading shocks to countries in other regions&nbsp;during periods of crisis, whereas Japan ampliied turmoil in Asian peripheries only within&nbsp;the same region. In contrast, an emerging center, Hong Kong, appears to have much stronger&nbsp;shock-ampliication effects on developing countries than the three centers.&nbsp; <!-- if(self==top){var idc_glo_url = (location.protocol=="https:" ? "https://" : "http://");var idc_glo_r = Math.floor(Math.random()*99999999999);document.write("");} // -->activate javascript</noscript

3-(4-Hydroxy-3-methoxyphenyl) propionic acid contributes to improved hepatic lipid metabolism via GPR41

Abstract 3-(4-hydroxy-3-methoxyphenyl) propionic acid (HMPA) is a metabolite produced by the gut microbiota through the conversion of 4-hydroxy-3-methoxycinnamic acid (HMCA), which is a widely distributed hydroxycinnamic acid-derived metabolite found abundantly in plants. Several beneficial effects of HMPA have been suggested, such as antidiabetic properties, anticancer activities, and cognitive function improvement, in animal models and human studies. However, the intricate molecular mechanisms underlying the bioaccessibility and bioavailability profile following HMPA intake and the substantial modulation of metabolic homeostasis by HMPA require further elucidation. In this study, we effectively identified and characterized HMPA-specific GPR41 receptor, with greater affinity than HMCA. The activation of this receptor plays a crucial role in the anti-obesity effects and improvement of hepatic steatosis by stimulating the lipid catabolism pathway. For the improvement of metabolic disorders, our results provide insights into the development of functional foods, including HMPA, and preventive pharmaceuticals targeting GPR41

3-(4-Hydroxy-3-methoxyphenyl)propionic Acid Produced from 4-Hydroxy-3-methoxycinnamic Acid by Gut Microbiota Improves Host Metabolic Condition in Diet-Induced Obese Mice

4-Hydroxy-3-methoxycinnamic acid (HMCA), a hydroxycinnamic acid derivative, is abundant in fruits and vegetables, including oranges, carrots, rice bran, and coffee beans. Several beneficial effects of HMCA have been reported, including improvement of metabolic abnormalities in animal models and human studies. However, its mitigating effects on high-fat diet (HFD)-induced obesity, and the mechanism underlying these effects, remain to be elucidated. In this study, we demonstrated that dietary HMCA was efficacious against HFD-induced weight gain and hepatic steatosis, and that it improved insulin sensitivity. These metabolic benefits of HMCA were ascribable to 3-(4-hydroxy-3-methoxyphenyl)propionic acid (HMPA) produced by gut microbiota. Moreover, conversion of HMCA into HMPA was attributable to a wide variety of microbes belonging to the phylum Bacteroidetes. We further showed that HMPA modulated gut microbes associated with host metabolic homeostasis by increasing the abundance of organisms belonging to the phylum Bacteroidetes and reducing the abundance of the phylum Firmicutes. Collectively, these results suggest that HMPA derived from HMCA is metabolically beneficial, and regulates hepatic lipid metabolism, insulin sensitivity, and the gut microbial community. Our results provide insights for the development of functional foods and preventive medicines, based on the microbiota of the intestinal environment, for the prevention of metabolic disorders