Washington University in St. Louis (WU)
We are interested in lipid metabolism and how it promotes atherosclerosis in the setting of obesity, insulin resistance and diabetes. Our work is translational, spanning cultured cells, animal models and humans. Fatty acid metabolism is controlled in part by the nuclear receptor perioxisome proliferator-activated receptor alpha (PPARalpha). We have demonstrated a role for this receptor in atherosclerosis, diabetes and hypertension in animal models and in blood pressure control in humans. Using tissue-specific inactivation of the rate-limiting enzyme in lipogenesis, fatty acid synthase (FAS), we have also shown that FAS generates an endogenous ligand responsible for PPARalpha activation. Ongoing studies are defining how FAS and PPARalpha interact to affect metabolism. Up to a quarter of Americans have some combination of abnormal lipids, high blood pressure, elevated blood sugar, and excess abdominal fat. Collectively, these conditions constitute the metabolic syndrome, which confers considerable risk for frank diabetes and cardiovascular disease. We have shown that a mutation in the kinase ATM, known to be responsible for the cancer-prone disease ataxia telangiectasia, contributes to features of the metabolic syndrome in mice. Low dose, intermittent administration of the anti-malarial drug chloroquine activates ATM and improves metabolic abnormalities in mice. Mechanistic studies in animal models and clinical trials in humans are testing the hypothesis that ATM activation ameliorates the metabolic syndrome.