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( Chengfu Xu ),( Xingyong Wan ),( Chaohui Yu ),( Lei Xu ),( Ming Yan ),( Honglei Weng ),( Min Miao ),( Yan Sun ),( Genyun Xu ),( Steven Dooley ),( William Coleman ),( Youming Li ) 대한내과학회 2014 대한내과학회 추계학술발표논문집 Vol.2014 No.1
Background: Hyperuricemia has been commonly found in patients with nonalcoholic fatty liver disease (NAFLD). This study aimed to clarify the causal relationship between NAFLD and hyperuricemia and to explore their underlying mechanisms. Methods: First, we evaluated the impact of NAFLD on development of hyperuricemia in a cohort of 5541 hyperuricemia-free individuals. Second, we analyzed the involvement of xanthine oxidase (XO), a rate-limiting enzyme catalyzes uric acid production, in the relationship between NAFLD and hyperuricemia in cultured HepG2 cells and a murine model of NAFLD. Results: In the first study, 7-year prospective analysis found that NAFLD was strongly associated with subsequent development of hyperuricemia. Cox proportional hazards regression analyses showed that the age, gender, and body mass index adjusted hazard ratio (95% CI) for incident hyperuricemia was 1.609 (1.129 - 2.294) in individuals with NAFLD compared with those without NAFLD. In the second study, we observed that the expression and activity of XO were significantly increased in cellular and mouse models of NAFLD. Knocking down XO expression or inhibiting XO activity significantly inhibited uric acid production and attenuated free fatty acids (FFA)-induced fat accumulation in HepG2 cells. Inhibition of XO activity also significantly decreased serum uric acid levels and ameliorated high fat diet-induced hepatic steatosis in mice. Further experiments indicated that XO regulates the activation of NLRP3 inflammasome, which may be essential for the regulatory effect of XO on NAFLD. Conclusions: XO promotes hyperuricemia and the development of NAFLD, which may serve as a novel therapeutic target for NAFLD.
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>
Noh, Jung-Ran,Kim, Yong-Hoon,Kim, Don-Kyu,Hwang, Jung Hwan,Kim, Kyoung-Shim,Choi, Dong-Hee,Lee, Seon-Jin,Lee, Hee Gu,Lee, Tae Geol,Weng, Hong-Lei,Dooley, Steven,Choi, Hueng-Sik,Lee, Chul-Ho ACADEMIC PRESS 2018 TOXICOLOGICAL SCIENCES Vol.163 No.1
<P>Although detailed pathophysiological mechanisms of fulminant hepatitis remain elusive, immune cell recruitment with excessive cytokine production is a well-recognized hallmark of the disease. We determined the function of orphan nuclear receptor small heterodimer partner (SHP) in concanavalin A (ConA)-induced hepatitis model. Male CS7BL/6 J mice were injected intravenously with either a lethal dose (25 mg/kg) or a sub-lethal dose (15 mg/kg) of ConA. For the C-X-C motif chemokine ligand (CXCL) 2 neutralization study, mice were intravenously administered anti-mouse CXCL2 antibody (100 mu g/mouse). Thirty-six hours following lethal dose of ConA administration, 47% wild type (WI) mice were alive, whereas >85% of Shp knockout (KO) were dead. Shp KO mice were highly susceptible to ConA-induced liver injury and exhibited increased liver necrosis upon sublethal dose of ConA administration. FACS analysis and immunohistochemical staining showed significantly higher neutrophil infiltration in Shp KO mice, as compared with WT mice. We found that also in the WT situation, Shp expression gradually decreased, while Cxcl2 expression increased until 6 h, and vice versa at 24 h upon ConA-treatment, indicating an inverse correlation between Shp and Cxcl2 expression during ConA-induced hepatitis. Furthermore, in vivo neutralization of CXCL2 with neutralizing antibody reduces ConA-induced plasma ALT and AST levels, hepatocyte death and neutrophil infiltration in Shp KO mice. Collectively, these results confirm that lacking of SHP results in CXCL2-dependent neutrophil infiltration in ConA-induced liver damage. SHP plays a protective, anti-inflammatory role in liver during acute liver inflammation.</P>