Acute liver failure (ALF) is a devastating condition with high mortality (60-80%), and liver transplantation is the only life-saving option for ALF due to the lack of early diagnostic indicator(s) and effective pharmacologic treatment. Incidence of drug-induced (acetaminophen [APAP] being most common) hepatotoxicity is very high in general and in particular VA populations, and accounts for about 15% of the liver transplants. Therefore, precise knowledge of the mechanisms and diagnostic indicators of ALF become critical to develop therapeutic interventions since the failing liver may revive if given proper treatment in a timely manner. There is compelling evidence for an association between increased endotoxin (lipopolysaccharide, LPS) and ALF. Alcoholism, incidence of which is high among veterans, pre-existing undiagnosed liver disease or even simple fever all increase LPS and can put these subjects at high risk of liver failure due to APAP. Indeed, chronic alcohol intake is more associated with APAP hepatotoxicity than fasting. Although APAP overdose increases probability of ALF, serious liver damage at therapeutic doses has also been observed, which may be due to preexisting condition such as elevated LPS. Mechanisms of such predisposition are poorly understood. Our research shows that the perisinusoidal hepatic stellate cells (HSCs) strongly react to very low concentrations of LPS and regulate hepatocyte survival via soluble mediators, and further indicates that HSCs regulate function of liver-resident macrophages, Kupffer cells. LPS-induced modest acute liver injury is ameliorated in a novel HSC-depleted mouse developed in our laboratory. However, excessive damage occurred when HSC-sufficient LPS-treated fed mice were challenged with otherwise tolerated dose of APAP. In contrast, HSC-depleted mice were protected from LPS/APAP-injury. This observation is highly significant as high dose APAP-induced liver injury is investigated almost exclusively in starved mice; starvation depletes hepatocytes of ATP and GSH rendering them vulnerable to excessive death. Our preliminary data indicate that IFN? released by LPS-stimulated HSCs is a critical mediator that induces activation of interferon-regulatory factor 1 (IRF1) in hepatocytes and conditions them to subsequent APAP-induced death. We also found that serum levels of a protein named ?Augmenter of Liver Regeneration (ALR)? are elevated prior to ALT or inflammatory cytokines in various models of acute liver injury. ALR is constitutively produced and secreted by hepatocytes and its mitochondrial presence is essential for their survival. Our in vitro and in vivo experiments show that LPS/HSC + APAP elicits greater ALR release by hepatocytes. Based on these findings, we propose to test the hypothesis that HSCs, directly and by modulating Kupffer cell responses, orchestrate liver failure in LPS-preconditioned mice by otherwise innocuous dose of APAP via the IFN?/IRF1 axis. We further hypothesize that serum ALR can be a reliable diagnostic biomarker for ongoing hepatocellular stress or injury.
Our AIMS are-- AIM 1: To investigate the role of HSCs in LPS/APAP-induced liver injury and that ALR is an early reliable serum biomarker for ALF.
AIM 2 : To delineate molecular mechanisms of APAP-induced hepatocyte death by LPS/HSC in vitro.
AIM 3 : To investigate the role of HSCs in modulating characteristics of Kupffer cells. The outcome of this investigation is expected to provide much improved understanding of the mechanisms of APAP-induced liver injury, with implications in alcoholism and other conditions that predispose the liver to excessive damage. We also expect to identify ALR as an early biomarker of APAP-induced injury. This knowledge may be useful in developing strategies for timely therapeutic intervention for ALF.

Public Health Relevance

Acute liver failure (ALF) due to drugs such as acetaminophen (available over the counter) is common among general and especially veteran populations. The morbidity and mortality due to ALF continue to be high, with liver transplantation as the only life-saving option. Despite extensive research, there is no known early diagnostic indicators and no effective pharmacologic treatment because the precise mechanisms of ALF are poorly understood. The current research, based on strong evidence from our laboratory, will apply a new approach to discover as yet unknown but critical mechanisms of ALF as well as early diagnostic indicator(s). It focuses on hepatic stellate cells and their interactions with other liver cells in orchestrating liver damage, and serum levels of a hepatocyte-specific protein for diagnosis of injury. Such knowledge will be highly significant for the development of new therapies to target HSCs or factor(s) thereof in order to prevent the ongoing hepatic damage responsible for morbidity and mortality due to ALF.

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Veterans Affairs (VA)
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Cincinnati VA Medical Center Research
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Rani, Richa; Kumar, Sudhir; Sharma, Akanksha et al. (2018) Mechanisms of concanavalin A-induced cytokine synthesis by hepatic stellate cells: Distinct roles of interferon regulatory factor-1 in liver injury. J Biol Chem 293:18466-18476
Sharma, Akanksha; Gandhi, Chandrashekhar R (2018) ""CHOP""ing intestinal stem cells on way to cholestatic liver injury. Hepatology 67:1216-1218
Yao, Lu; Chen, Weina; Song, Kyoungsub et al. (2017) 15-hydroxyprostaglandin dehydrogenase (15-PGDH) prevents lipopolysaccharide (LPS)-induced acute liver injury. PLoS One 12:e0176106
Gandhi, Chandrashekhar R (2017) Hepatic stellate cell activation and pro-fibrogenic signals. J Hepatol 67:1104-1105
Nalesnik, Michael A; Gandhi, Chandrashekhar R; Starzl, Thomas E (2017) Augmenter of liver regeneration: A fundamental life protein. Hepatology 66:266-270
Kumar, Sudhir; Wang, Jiang; Thomson, Angus W et al. (2017) Hepatic stellate cells increase the immunosuppressive function of natural Foxp3+ regulatory T cells via IDO-induced AhR activation. J Leukoc Biol 101:429-438
Rani, Richa; Tandon, Ashish; Wang, Jiang et al. (2017) Stellate Cells Orchestrate Concanavalin A-Induced Acute Liver Damage. Am J Pathol 187:2008-2019
Kumar, Sudhir; Wang, Jiang; Shanmukhappa, Shiva Kumar et al. (2017) Toll-Like Receptor 4-Independent Carbon Tetrachloride-Induced Fibrosis and Lipopolysaccharide-Induced Acute Liver Injury in Mice: Role of Hepatic Stellate Cells. Am J Pathol 187:1356-1367
Vodovotz, Yoram; Simmons, Richard L; Gandhi, Chandrashekhar R et al. (2017) ""Thinking"" vs. ""Talking"": Differential Autocrine Inflammatory Networks in Isolated Primary Hepatic Stellate Cells and Hepatocytes under Hypoxic Stress. Front Physiol 8:1104
Shoukry, Naglaa H; Fabre, Thomas; Gandhi, Chandrashekhar R (2016) A novel role for hepatic stellate cells in pathogenesis of visceral leishmaniasis. Hepatology 63:375-6

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