The Role of Lipocalin-2 (Lcn2) in Acetaminophen-Induced Acute Liver Failure

Date of Award

6-2017

Degree Type

Thesis

Degree Name

Master of Science in Biomedical Sciences

First Advisor

Vishakha Bhave, PhD

Second Advisor

Rangaiah Shashidharamurthy, PhD

Third Advisor

Srujana Rayalam, PhD

Fourth Advisor

Bonnie Buxton, PhD

Fifth Advisor

Richard White, PhD

Abstract

Acetaminophen (AP AP) toxicity is the number one cause of acute liver failure (ALF), and treatment options are limited. The initial toxicity is caused by the bio-activation of the drug to the reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI). This initial toxicity continues to expand and progress even after the drug has been eliminated from the body. The mechanisms underlying this progressive phase of injury in the absence of the drug that causes it are not completely understood. APAP overdose involves sterile inflammation. This inflammation is required for clearance of necrotic debris following initial drug-induced injury. Lipocalin-2 (Lcn2) is an innate immune protein that is upregulated in various disease models and has been observed to have a protective as well as destructive role dependent on the model analyzed. Studies have shown that Lcn2 acts as an anti-inflammatory modulator in low doses of toxicity, when pro-mitogenic signaling is activated. In contrast, these repair and regeneration pathways are shown to be inhibited in a high dose model of toxicity, which ultimately leads to acute liver failure. The role of Lcn2 in a high dose model of toxicity has not yet been investigated. This study aimed to investigate the role of Lcn2 in a drug induced acute liver failure (APAP overdose) model and the mechanism of its involvement. An in vivo model of acute liver failure was utilized and Lcn2 KO mice were used as our intervention. We hypothesized that Lcn2 KO mice will be protected from APAP induced acute liver failure. Our preliminary survival studies demonstrated 20% lethality in Lcn2 KO mice and 60% lethality in WT mice subjected to AP P overdose suggesting that Lcn2 KO were protected against APAP-induced acute liver failure. Time course studies were done over a period of0-96 hours post-AP AP overdose to investigate the mechanism of this protection. Liver tissue and serum were harvested at each time point. Liver injury as assessed by ALT and AST levels was higher in WT mice compared to Lcn2 KO mice corroborating the protection ofLcn2 KO mice against ALF. Cyp2El and Cyp3A4 protein expression and GSH depletion and replenishment between WT and Lcn2 KO mice was comparable, indicating that the difference in susceptibility between the WT and Lcn2 KO mice was not due to difference in bioactivation of APAP to the toxic metabolite, but rather due difference in progression of injury at later time points. Proliferating cell nuclear antigen (Pena) protein expression analysis indicated that Lcn2 KO expressed more PCNA compared to WT, indicating that Lcn2 KO livers were regenerating and recovering more efficiently as compared to the WT mice. In conclusion, Lcn2 likely plays a role in mediating progression of injury in a drug overdose model of ALF.

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