Fatty Acid Oxidation in Regulation of Drug Hepatotoxicity

Va Veterans Administration Hospital, Richmond VA

Investigators

Linked publications & trials

Abstract

SUMMARY The acetaminophen (APAP) overdose or abuse that causes severe liver injury and failure remains a great threat to the general population and veterans. A better mechanistic understanding of APAP-induced liver injury (AILI) and liver regeneration after drug insult will help advance therapeutic development to improve outcomes. Although dysregulated fatty acid oxidation (FAO) has been implicated in multiple liver diseases, its exact role in drug hepatotoxicity including AILI remains elusive. We discovered that inhibition of FAO or its rate-limiting enzyme carnitine palmitoyltransferase 1A (CPT1A) exacerbated AILI and also impaired liver recovery whereas enhancing FAO provides significant hepatoprotection. Our findings suggest that metabolic activation of FAO serves as a crucial regulator governing liver homeostasis in APAP hepatoxicity. Intriguingly, this CPT1A-FAO machinery actively operates with distinct functions in both hepatocytes and liver-resident macrophages. The objective of this project is to interrogate the CPT1A-FAO pathway in regulation of the highly integrated molecular and cellular processes in liver injury as well as regeneration, a critical determinant of the final outcome. We will establish an under-appreciated role of hepatocyte autonomous FAO for counteracting APAP-triggered cytotoxic stress and especially for driving hepatocellular renewal during tissue recovery. In addition, using models with CPT1A selectively deleted in macrophages and other tools, we will determine a previously unrecognized role of FAO in functionally skewing these myeloid cells to attenuate abnormal hepatic inflammation and accelerate the tissue regenerative process. Currently, N-acetylcysteine, which has limited benefits, is the only treatment option for APAP overdose. In this application, we will also evaluate a novel AMP-activated protein kinase agonist for reprogramming hepatic FAO activity to mitigate APAP hepatoxicity while concurrently stimulating liver regeneration. These comprehensive studies will advance our understanding of a new mechanism that defines the pathogenesis of AILI and help identify novel targets for drug discovery. Our research is highly significant and clinically relevant because successful development of the innovative FAO-modifying treatment to manage APAP overdose can broaden therapeutic benefits to the general public and veterans.