There is little doubt that we are in the midst of a worldwide epidemic of obesity and diabetes. Among the many
complications of obesity is fatty liver, and its associated disease Nonalcoholic Steatotic Hepatitis (NASH).
However, the manner by which lipid storage and oxidation is controlled in liver is only partly understood. We
hypothesize that inflammation plays a role in this process through the protein kinase TBK1. TBK1 associates
with the key enzyme ACSL1, localizing it to mitochondria for fatty acid oxidation during starvation, and to ER
for fatty acid re-esterification during obesity. Moreover, TBK1 represses the activity of AMPK during obesity,
linking fatty liver to liver damage. We will explore the nature of these pathways with three aims: 1) We will
elucidate the temporal and spatial aspects of the induction and activation of the kinase TBK1 in fasting and
obesity; 2) We will deeply explore the molecular mechanism involved in its interaction with ACSL1; and 3) We
will evaluate the molecular mechanisms whereby TBK1 reduces the activity of AMPK, and how this results in
hepatocellular death and liver damage.