Acute Injury in Natural Diet-Induced Fatty Livers - A Model for Therapy Development

Authors

Brian Huang, Nicholas A. E. Abbott, Linai Dacon, Siobhan McCormack, Ping Zhou, Liming Zhang, Bin Duan, Jingsong Li, Bo Zhang, Michael Yamin, Latha Paka, Itzhak D. Goldberg and Prakash Narayan

Abstract

Given the diabesity and Metabolic Syndrome epidemics, fatty liver disease is reaching epidemic proportions. Relatively indolent, this disease is often asymptomatic and the patient is often made aware of its presence only during a routine physical exam. Nevertheless, fatty livers are more susceptible to insult compared to their non-fatty counterparts and persons with fatty livers are at increased risk for morbidity and mortality following consumption of commonly used substances such as alcohol (EtOH) and acetaminophen (APAP). We have developed a rat model of natural diet-induced fatty liver disease and evaluated the effects of two commonly used substances viz. EtOH and APAP in this phenotype. High fat diet (HFD) fed animals exhibited steatosis, liver inflammation and liver fibrosis with an increase in serum aspartate aminotransferase. Bolus administration of EtOH, which was without effect on the livers from standard diet fed animals, had a profound and adverse impact on the HFD fatty liver. Similarly, APAP administration which was without effect on liver function tests in control animals, also provoked an increase in liver enzymes in HFD animals. Treatment with the poly(ADP-ribose) polymerase-1 inhibitor (PARP-1), veliparib, reduced the increase in liver function tests secondary to EtOH and APAP. This model forms the framework for identification of fatty liver disease biomarkers given that this disease is relatively asymptomatic but fraught with risk for acute injury. This model also forms the framework for evaluation of novel drugs for acute injury in fatty livers especially given that current strategies for management of acute liver failure in non-fatty livers are inadequate. Also, relevant patents related to the use of liver biomarkers as diagnostic are discussed.