Browsing by Author "Sehrawat, Tejasav S."

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    Hepatic stellate cell activation promotes alcohol-induced steatohepatitis through Igfbp3 and SerpinA12
    (2020) Arab, Juan P.; Cabrera, Daniel; Sehrawat, Tejasav S.; Jalan-Sakrikar, Nidhi; Verma, Vikas K.; Simonetto, Douglas; Cao, Sheng; Yaqoob, Usman; Leon, Jonathan; Freire, Mariela; Vargas, Jose, I; De Assuncao, Thiago M.; Kwon, Jung H.; Guo, Yi; Kostallari, Enis; Cai, Qing; Kisseleva, Tatiana; Oh, Youngman; Arrese, Marco; Huebert, Robert C.; Shah, Vijay H.
    Background & Aims: Steatohepatitis drives fibrogenesis in alcohol-related liver disease. Recent studies have suggested that hepatic stellate cells (HSCs) may regulate the parenchymal cell injury and inflammation that precedes liver fibrosis, although the mechanism remains incompletely defined. Neuropilin-1 (NRP-1) and synectin are membrane proteins implicated in HSC activation. In this study, we disrupted NRP-1 and synectin as models to evaluate the role of HSC activation on the development of steatohepatitis in response to alcohol feeding in mice.
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    Super enhancer regulation of cytokine-induced chemokine production in alcoholic hepatitis
    (2021) Liu, Mengfei; Cao, Sheng; He, Li; Gao, Jinhang; Arab, Juan P.; Cui, Huarui; Xuan, Weixia; Gao, Yandong; Sehrawat, Tejasav S.; Hamdan, Feda H.; Ventura-Cots, Meritxell; Argemi, Josepmaria; Pomerantz, William C. K.; Johnsen, Steven A.; Lee, Jeong-Heon; Gao, Fei; Ordog, Tamas; Mathurin, Philippe; Revzin, Alexander; Bataller, Ramon; Yan, Huihuang; Shah, Vijay H.
    Alcoholic hepatitis (AH) is associated with liver neutrophil infiltration through activated cytokine pathways leading to elevated chemokine expression. Super-enhancers are expansive regulatory elements driving augmented gene expression. Here, we explore the mechanistic role of super-enhancers linking cytokine TNF alpha with chemokine amplification in AH. RNA-seq and histone modification ChIP-seq of human liver explants show upregulation of multiple CXCL chemokines in AH. Liver sinusoidal endothelial cells (LSEC) are identified as an important source of CXCL expression in human liver, regulated by TNF alpha /NF-kappa B signaling. A super-enhancer is identified for multiple CXCL genes by multiple approaches. dCas9-KRAB-mediated epigenome editing or pharmacologic inhibition of Bromodomain and Extraterminal (BET) proteins, transcriptional regulators vital to super-enhancer function, decreases chemokine expression in vitro and decreases neutrophil infiltration in murine models of AH. Our findings highlight the role of super-enhancer in propagating inflammatory signaling by inducing chemokine expression and the therapeutic potential of BET inhibition in AH treatment. Alcoholic hepatitis is characterized by intense liver inflammation driven by excessive cytokines and chemokines production and immune cell infiltration. Here the authors identify a super-enhancer that regulates the expression of multiple CXCL chemokines in alcoholic hepatitis and may be a potential therapeutic target.
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    XIAP Knockdown in Alcohol-Associated Liver Disease Models Exhibits Divergent in vitro and in vivo Phenotypes Owing to a Potential Zonal Inhibitory Role of SMAC
    (2021) He, Li; Sehrawat, Tejasav S.; Verma, Vikas K.; Navarro-Corcuera, Amaia; Sidhu, Guneet; Mauer, Amy; Luo, Xin; Katsumi, Tomohiro; Chen, Jingbiao; Shah, Soni; Arab, Juan Pablo; Cao, Sheng; Kashkar, Hamid; Gores, Gregory J.; Malhi, Harmeet; Shah, Vijay H.
    Alcohol-associated liver disease (ALD) has been recognized as the most common cause of advanced liver disease worldwide, though mechanisms of pathogenesis remain incompletely understood. The X-linked inhibitor of apoptosis (XIAP) protein was originally described as an anti-apoptotic protein that directly binds and inhibits caspases-3, 7, and 9. Here, we investigated the function of XIAP in hepatocytes in vitro using gain and loss-of-function approaches. We noted an XIAP-dependent increase in caspase activation as well as increased inflammatory markers and pro-inflammatory EV release from hepatocytes in vitro. Primary hepatocytes (PMH) from Xiap(Alb.Cre) and Xiap(loxP) mice exhibited higher cell death but surprisingly, lower expression of inflammation markers. Conditioned media from these isolated Xiap deleted PMH further decrease inflammation in bone marrow-derived macrophages. Also, interestingly, when administered an ethanol plus Fas-agonist-Jo2 model and an ethanol plus CCl4 model, these animals failed to develop an exacerbated disease phenotype in vivo. Of note, neither Xiap(Alb).(Cre) nor Xiap(AAV8.Cre) mice presented with aggravated liver injury, hepatocyte apoptosis, liver steatosis, or fibrosis. Since therapeutics targeting XIAP are currently in clinical trials and caspase-induced death is very important for development of ALD, we sought to explore the potential basis of this unexpected lack of effect. We utilized scRNA-seq and spatially reconstructed hepatocyte transcriptome data from human liver tissue and observed that XIAP was significantly zonated, along with its endogenous inhibitor second mitochondria-derived activator of caspases (SMAC) in periportal region. This contrasted with pericentral zonation of other IAPs including cIAP1 and Apollon as well as caspases 3, 7, and 9. Thus providing a potential explanation for compensation of the effect of Xiap deletion by other IAPs. In conclusion, our findings implicate a potential zonallydependent role for SMAC that prevented development of a phenotype in XIAP knockout mice in ALD models. Targeting SMAC may also be important in addition to current efforts of targeting XIAP in treatment of ALD.