Acute liver failure (ALF) is characterized by severe and sudden loss of hepatocellular function in patients with previously normal liver function which may lead to multiorgan system failure and death. In the US, drug- induced liver injury is the main cause of ALF, and acetaminophen (APAP) intoxication accounts for ~50% of ALF cases. APAP-induced ALF disproportionally affects children, adolescents and young adults. N-acetyl- cysteine is the only currently available therapy for APAP-induced ALF; however, it is not completely effective with a mortality rate of 30% and another 10% requiring liver transplant. Therefore, alternative or complemen- tary pharmacological therapies are desperately needed for individuals, especially children, suffering from APAP-induced ALF. MicroRNAs (miRNAs) have been implicated in liver inflammation, fibrosis, and viral infection. MiRNAs are highly attractive therapeutic targets on their way into the clinic, but the role of miRNAs as therapeutic agents in APAP-induced ALF remains unexplored. MicroRNA-21 (miR-21) is an attractive candi- date because it is one of the most highly expressed hepatic miRNAs and is dynamically regulated by APAP overdose. Furthermore, in patients with spontaneous recovery from ALF, miR-21 expression is decreased in liver biopsies, strongly suggesting that reduction of hepatic miR-21 levels may be a valid therapeutic approach for APAP-ALF. One mechanism by which miR-21 reduction is protective against APAP-ALF may be due to changes in liver zonation. Liver zonation is critical for ammonia detoxification, glucose/ energy metabolism, and xenobiotic metabolism. Pharmacological manipulation of specific hepatic miRNAs could lead to transient liver zonation disruption that may protect against APAP-induced ALF. We have preliminary data that miR-21 genetic ablation in mice protects against APAP-induced ALF, with attenuation of APAP-mediated increases in serum hepatic enzymes and reduced liver necrosis. Furthermore, miR-21 over-expression in transgenic mice exacerbates the APAP-induced liver injury. We also have preliminary data that miR-21 is preferentially expressed in periportal hepatocytes. In addition, miR-21 ablation disrupts the expression pattern of hepatic glutamine synthetase, suggesting that the lack of miR-21 leads to a periportal-like liver phenotype that may also contribute to the protective effect of miR-21 downregulation in APAP-induced ALF. Based on these exciting preliminary data, we propose to test the central hypothesis that ?miR-21 regulates liver zonation, and downregulation of miR-21 leads to a periportal-like liver phenotype that protects against APAP-induced hepatotoxicity.? This hypothesis will be tested in the following specific aims: 1) To test the hypothesis that miR-21 ablation protects against, while miR-21 over-expression exacerbates, APAP-induced hepatotoxicity; 2) To test the hypothesis that acute pharmacological downregulation of miR-21 protects against APAP-induced acute liver failure; 3) To test the hypothesis that miR-21 is preferentially expressed in periportal hepatocytes and regulates liver zonation thereby modulating APAP-induced hepatotoxicity.
The proposed research is relevant to the public health since the elucidation of the molecular mechanisms that mediate drug-induced liver injury will lead to the development of novel therapeutic approaches for the clinical management of life threatening acute liver failure. Manipulation of hepatic microRNA-21 levels may provide a novel therapeutic approach for the treatment of acetaminophen-induced acute liver injury, the main cause of acute liver failure in the US. Thus, the proposed research is relevant to the NIH's mission to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability.
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