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WDR11‐mediated Hedgehog signalling defects underlie a new ciliopathy related to Kallmann syndrome
Kim, Yeon‐,Joo,Osborn, Daniel PS,Lee, Ji‐,Young,Araki, Masatake,Araki, Kimi,Mohun, Timothy,Kä,nsä,koski, Johanna,Brandstack, Nina,Kim, Hyun‐,Taek,Miralles, Francesc,Kim, Cheo John Wiley and Sons Inc. 2018 EMBO reports Vol.19 No.2
<P><B>Abstract</B></P><P>WDR11 has been implicated in congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS), human developmental genetic disorders defined by delayed puberty and infertility. However, WDR11's role in development is poorly understood. Here, we report that WDR11 modulates the Hedgehog (Hh) signalling pathway and is essential for ciliogenesis. Disruption of WDR11 expression in mouse and zebrafish results in phenotypic characteristics associated with defective Hh signalling, accompanied by dysgenesis of ciliated tissues. <I>Wdr11</I>‐null mice also exhibit early‐onset obesity. We find that WDR11 shuttles from the cilium to the nucleus in response to Hh signalling. WDR11 regulates the proteolytic processing of GLI3 and cooperates with the transcription factor EMX1 in the induction of downstream Hh pathway gene expression and gonadotrophin‐releasing hormone production. The CHH/KS‐associated human mutations result in loss of function of WDR11. Treatment with the Hh agonist purmorphamine partially rescues the WDR11 haploinsufficiency phenotypes. Our study reveals a novel class of ciliopathy caused by WDR11 mutations and suggests that CHH/KS may be a part of the human ciliopathy spectrum.</P>
Kim, Don-Kyu,Kim, Yong-Hoon,Lee, Jae-Ho,Jung, Yoon Seok,Kim, Jina,Feng, Rilu,Jeon, Tae-Il,Lee, In-Kyu,Cho, Sung Jin,Im, Seung-Soon,Dooley, Steven,Osborne, Timothy F.,Lee, Chul-Ho,Choi, Hueng-Sik Elsevier 2019 Biochimica et biophysica acta, Molecular and cell Vol.1864 No.12
<P><B>Abstract</B></P> <P>Although SREBP-1c regulates key enzymes required for hepatic <I>de novo</I> lipogenesis, the mechanisms underlying transcriptional regulation of SREBP-1c in pathogenesis of alcoholic fatty liver is still incompletely understood. In this study, we investigated the role of ERRγ in alcohol-mediated hepatic lipogenesis and examined the possibility to ameliorate alcoholic fatty liver through its inverse agonist. Hepatic ERRγ and SREBP-1c expression was increased by alcohol-mediated activation of CB<SUB>1</SUB> receptor signaling. Deletion and mutation analyses of the <I>Srebp-1c</I> gene promoter showed that ERRγ directly regulates <I>Srebp-1c</I> gene transcription <I>via</I> binding to an ERR-response element. Overexpression of ERRγ significantly induced SREBP-1c expression and fat accumulation in liver of mice, which were blocked in <I>Srebp-1c</I>-knockout hepatocytes. Conversely, liver-specific ablation of <I>ERRγ</I> gene expression attenuated alcohol-mediated induction of SREBP-1c expression. Finally, an ERRγ inverse agonist, GSK5182, significantly ameliorates fatty liver disease in chronically alcohol-fed mice through inhibition of SREBP-1c-mediated fat accumulation. ERRγ mediates alcohol-induced hepatic lipogenesis by upregulating SREBP-1c expression, which can be blunted by the inverse agonist for ERRγ, which may be an attractive therapeutic strategy for the treatment of alcoholic fatty liver disease in human.</P> <P><B>Highlights</B></P> <P> <UL> <LI> ERRγ is induced by alcohol-mediated activation of CB<SUB>1</SUB> receptor signaling. </LI> <LI> ERRγ increases hepatic SREBP-1c expression and alcohol-mediated hepatic lipogenesis </LI> <LI> An ERRγ inverse agonist inhibits SREBP-1c-induced hepatic <I>de novo</I> lipogenesis. </LI> <LI> An ERRγ inverse agonist ameliorates alcohol fatty liver disease. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Jae-Ho Lee,고영훈,Do-Young Kim,Sun Hee Lee,김옥희,Yong Hyun Jeon,권택규,Jae-Hoon Bae,Dae Kyu Song,Im Joo Rhyu,In-Kyu Lee,송민호,오병철,Christopher Petucci,Jeen-Woo Park,Timothy F. Osborne,임승순 생화학분자생물학회 2020 Experimental and molecular medicine Vol.52 No.-
Isocitrate dehydrogenase 2 (IDH2) is an NADP+-dependent enzyme that catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate in the mitochondrial matrix, and is critical for the production of NADPH to limit the accumulation of mitochondrial reactive oxygen species (ROS). Here, we showed that high-fat diet (HFD) feeding resulted in accelerated weight gain in the IDH2KO mice due to a reduction in whole-body energy expenditure. Moreover, the levels of NADP+, NADPH, NAD+, and NADH were significantly decreased in the brown adipose tissue (BAT) of the HFD-fed IDH2KO animals, accompanied by decreased mitochondrial function and reduced expression of key genes involved in mitochondrial biogenesis, energy expenditure, and ROS resolution. Interestingly, these changes were partially reversed when the antioxidant butylated hydroxyanisole was added to the HFD. These observations reveal a crucial role for IDH2 in limiting ROS-dependent mitochondrial damage when BAT metabolism is normally enhanced to limit weight gain in response to dietary caloric overload.
Desiree F Baaleman,Mana H Vriesman,,Ilan J N Koppen,Kim M Osborne,Marc A Benninga,Miguel Saps,Desale Yacob,Peter L Lu,Frederick W Woodley,Carlo Di Lorenzo 대한소화기 기능성질환∙운동학회 2022 Journal of Neurogastroenterology and Motility (JNM Vol.28 No.2
Background/AimsTo assess the effectiveness and feasibility of a brief session of hypnosis to reduce distress in children with functional constipation undergoing anorectal manometry (ARM). MethodsA partially-blinded randomized controlled pilot trial was conducted in children 4-18 years old scheduled for ARM. Children were randomized to receive a brief session of hypnosis prior to ARM or standard care. Non-blinded and blinded observers rated the child’s level of distress using the Observation Scale of Behavioral Distress and a 4-point-Likert scale, respectively. Differences between groups were analyzed using Fisher’s exact test or Mann-Whitney U test as appropriate. ResultsData from 32 children (15 hypnosis and 17 standard care) were analyzed. Prior to insertion of the catheter, the observed mean levels of distress were lower in the hypnosis group according to both the non-blinded observer (median 0.0 [interquartile range {IQR} 0.0-0.3] vs 1.4 [IQR 0.3-2.4]; P = 0.009) and the blinded observer (median 0.0 [IQR 0.0-0.0] vs 0.5 [IQR 0.0-1.0]; P = 0.044). During ARM, observed and reported levels of distress did not differ significantly. In the hypnosis group, 92.9% of parents and children reported that hypnosis helped the child to relax. There were no significant differences in resting pressure, squeeze pressure, or duration of the procedure between both groups. ConclusionA brief session of hypnosis for children before ARM is an easily incorporable intervention that lowers distress levels prior to the procedure and is positively perceived by children and parents.