Nuclear ATP citrate lyase and ischemia/reperfusion injury in steatotic liver

Abstract Non-alcoholic fatty liver disease represents a group of conditions associated with excessive lipid accumulation in hepatocytes because of long-term energy surplus. This disease increases morbidity and mortality associated with injury or physiological stress, and thus is a concern for all medical disciplines. Our preliminary studies have identified a novel molecular mechanism that couples cellular energy metabolism to hepatocellular protection. Our studies demonstrate that ATP citrate lyase (ACLY), one of the two enzymes responsible for the synthesis of cytosolic acetyl-CoA, can translocate to the nuclei in hepatocytes. Impairment of ACLY nuclear translocation increases the vulnerability of hepatocytes to injury. AMP-activated protein kinase (AMPK)-mediated phosphorylation of ACLY is essential for its nuclear translocation. Our preliminary data also indicate that R- spondin 1 and 3, the endogenous ligands for leucine-rich repeat-containing G-protein-coupled receptors (LGR) secreted by hepatocytes, promote the ACLY nuclear translocation which subsequently ameliorates the vulnerability to injury associated with liver steatosis. We propose four Aims to investigate the function of ACLY in hepatic protection using cell biological and transgenic techniques. Aim 1 will define ACLY nuclear translocation as a novel mechanism accountable for the protection of hepatocytes from injury. Aim 2 will determine the epigenetic mechanism responsible for the hepatic protection of nuclear ACLY. Aim 3 will demonstrate that AMPK is critical for the phosphorylation of ACLY and its subsequent nuclear translocation. Aim 4 will examine whether R-spondin1/3-LGR4 signaling, identified as an endogenous system critical for hepatocellular protection by our previous studies, restores the impairment of ACLY nuclear translocation in steatotic liver. Completion of this proposal will advance a completely new area of hepatic physiology and will provide novel insights into liver injury.