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( Sungsoon Fang ) 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1
Dysregulation of hepatic lipid metabolism results in the development of hepatic steatosis, contributing to the chronic insulin resistance and steatotic hepatitis. The hepatic metabolic pathways are governed by highly dynamic transcriptional networks of orphan nuclear receptors (ONRs), including PPARs, farnesoid X receptor (FXR), and liver X receptor (LXR). ONRs are ligand-activated transcription factors with no defined ligands. Many ONRs are expressed in tissues involved in metabolism, such as skeletal muscle, adipose tissue, and liver, and play critical roles in the regulation of metabolism. Genetic studies have shown that many ONRs regulate nutrient metabolism and physiology of obesity and type II diabetes. Given that numerous synthesized ligands for ONRs are used for developing putative drugs for human metabolic diseases. ONRs are emerging as therapeutic targets for the treatment of metabolic diseases. Previously, we have reported that RORα, a member of ONRs, possesses tumor suppressive function by transrepressing canonical Wnt/β-catenin signaling leading to inhibition of colon cancer growth and by increasing p53 stability upon DNA damage response. RORα is known to regulate cerebellum development. The staggerer (sg) mice, natural Rorα spontaneous mutant mice, display ataxia and severe cerebellar atrophy. Moreover, RORα functions to regulate circadian rhythm as a key regulator of the cyclic expression of BMAL1 together with REV-ERBα. The RORα/REV-ERBα feedback loop controls the circadian expression pattern of BMAL1, indicating that RORα plays a key role in the core circadian clock. In addition, sg mice show lower expression levels of genes involved in lipid metabolism, including apolipoprotein A-1 (apoA1) and apolipoprotein C-III (apoCIII). Thus, sg mice exhibit less body weight gain compared with wild-type (WT) mice. Given that sg mice have huge cerebellar defects, it is still possible that physiological changes observed in sg mice are indirect effects. Thus, the physiological roles of RORα to control transcriptional networks to modulate lipogenesis and gluconeogenesis still remain unclear. We report that RORα plays a key role to control hepatic lipid metabolism to protect against diet-induced obesity and hepatic steatosis, using liver-specific Rorα deficient mouse model. High-fat diet (HFD)-fed liver-specific Rorα deficient mice (RORαLKO mice) show severe metabolic defects, including hepatic steatosis, obesity, and insulin resistance, although no physiological changes have been observed with control diet (CD). Genome-wide transcriptome analysis reveals that PPARγ signaling is remarkably elevated in RORαLKO mice. RORα specifically recruits HDAC3 to the PPARγ target promoters to suppress PPARγ transcriptional activity. Finally, PPARγ antagonism by using PPARγ antagonist GW9662, largely ameliorates body weight gain and hepatic steatosis in HFD-fed RORαLKO mice, indicating that dysregulated PPARγ signaling is a critical metabolic cue, leading to metabolic defects in HFD-fed RORαLKO mice. Together, our data demonstrate that RORα controls PPARγ signaling to protect against hepatic metabolic homeostasis and obesity in response to HFD.
GPx7 ameliorates non-alcoholic steatohepatitis by regulating oxidative stress
Hyeon Ju Kim,Yoseob Lee,Sungsoon Fang,김원,김효정,김재우 생화학분자생물학회 2020 BMB Reports Vol.53 No.6
Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases. NAFLD can further progress to irreversible liver failure such as non-alcoholic steatohepatitis (NASH) fibrosis and cirrhosis. However, specific regulator of NASHfibrosis has yet to be established. Here, we found that glutathione peroxidase 7 (GPx7) was markedly expressed in NASH fibrosis. Although GPx7 is an antioxidant enzyme protecting other organs, whether GPx7 plays a role in NASH fibrosis has yet to be studied. We found that knockdown of GPx7 in transforming growth factor- (TGF-) and free fatty acids (FFA)- treated LX-2 cells elevated the expression of pro-fibrotic and pro-inflammatory genes and collagen synthesis. Consistently, GPx7 overexpression in LX-2 cells led to the suppression of ROS production and reduced the expression of pro-fibrotic and pro-inflammatory genes. Further, NASH fibrosis induced by choline-deficient amino acid defined, high fat diet (CDAHFD) feeding was significantly accelerated by knockdown of GPx7, as evidenced by up-regulated liver fibrosis and inflammation compared with CDAHFD control mice. Collectively, these results suggest that GPx7 might be a novel therapeutic target to prevent the progression and development of NAFLD.
FXR Regulates Intestinal Cancer Stem Cell Proliferation
Fu, Ting,Coulter, Sally,Yoshihara, Eiji,Oh, Tae Gyu,Fang, Sungsoon,Cayabyab, Fritz,Zhu, Qiyun,Zhang, Tong,Leblanc, Mathias,Liu, Sihao,He, Mingxiao,Waizenegger, Wanda,Gasser, Emanuel,Schnabl, Bernd,Atk Elsevier 2019 Cell Vol.176 No.5
<P><B>Summary</B></P> <P>Increased levels of intestinal bile acids (BAs) are a risk factor for colorectal cancer (CRC). Here, we show that the convergence of dietary factors (high-fat diet) and dysregulated WNT signaling (APC mutation) alters BA profiles to drive malignant transformations in Lgr5-expressing (Lgr5<SUP>+</SUP>) cancer stem cells and promote an adenoma-to-adenocarcinoma progression. Mechanistically, we show that BAs that antagonize intestinal farnesoid X receptor (FXR) function, including tauro-β-muricholic acid (T-βMCA) and deoxycholic acid (DCA), induce proliferation and DNA damage in Lgr5<SUP>+</SUP> cells. Conversely, selective activation of intestinal FXR can restrict abnormal Lgr5<SUP>+</SUP> cell growth and curtail CRC progression. This unexpected role for FXR in coordinating intestinal self-renewal with BA levels implicates FXR as a potential therapeutic target for CRC.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Genetic and dietary risk factors for colorectal cancer converge on the BA-FXR axis </LI> <LI> FXR controls proliferating Lgr5<SUP>+</SUP> intestinal stem cells </LI> <LI> FXR agonists curtail colorectal cancer progression </LI> </UL> </P> <P><B>Graphical Abstract</B></P> <P>[DISPLAY OMISSION]</P>
윤보경,Tae Gyu Oh,부성현,서경진,권세환,Ji Yoon Lee,Yeumin Kim,김재우,Hyo-Suk Ahn,Sungsoon Fang 한국분자세포생물학회 2022 Molecules and cells Vol.45 No.10
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has posed a serious threat to global public health. A novel vaccine made from messenger RNA (mRNA) has been developed and approved for use at an unprecedented pace. However, an increased risk of myocarditis has been reported after BNT162b2 mRNA vaccination due to unknown causes. In this study, we used single-cell RNA sequencing and single-cell T cell receptor sequencing analyses of peripheral blood mononuclear cells (PBMCs) to describe, for the first time, changes in the peripheral immune landscape of a patient who underwent myocarditis after BNT162b2 vaccination. The greatest changes were observed in the transcriptomic profile of monocytes in terms of the number of differentially expressed genes. When compared to the transcriptome of PBMCs from vaccinated individuals without complications, increased expression levels of IL7R were detected in multiple cell clusters. Overall, results from this study can help advance research into the pathogenesis of BNT162b2-induced myocarditis.
Hwang Nahee,Yoon Bo Kyung,Chun Kyu-Hye,Kim Hyeonhui,Lee Yoseob,Kim Jae-Won,Jeon Hyeonuk,Kim Tae-Hyun,Kim Mi-Young,Fang Sungsoon,Cheong Jae-Ho,Kim Jae-woo 생화학분자생물학회 2023 Experimental and molecular medicine Vol.55 No.-
Despite advances in cancer therapy, the clinical outcome of patients with gastric cancer remains poor, largely due to tumor heterogeneity. Thus, finding a hidden vulnerability of clinically refractory subtypes of gastric cancer is crucial. Here, we report that chemoresistant gastric cancer cells rely heavily on endocytosis, facilitated by caveolin-1, for survival. caveolin-1 was highly upregulated in the most malignant stem-like/EMT/mesenchymal (SEM)-type gastric cancer cells, allowing caveolin-1-mediated endocytosis and utilization of extracellular proteins via lysosomal degradation. Downregulation of caveolin-1 alone was sufficient to induce cell death in SEM-type gastric cancer cells, emphasizing its importance as a survival mechanism. Consistently, chloroquine, a lysosomal inhibitor, successfully blocked caveolin-1-mediated endocytosis, leading to the marked suppression of tumor growth in chemorefractory gastric cancer cells in vitro, including patient-derived organoids, and in vivo. Together, our findings suggest that caveolin-1-mediated endocytosis is a key metabolic pathway for gastric cancer survival and a potential therapeutic target.