Dysregulation of lipoprotein metabolism may contribute to the excess atherosclerosis in individuals with the metabolic syndrome. This condition is characterized by multiple defects in lipoprotein metabolism, including increases in triglyceride-rich lipoproteins (TRLs). Insulin resistance and hyperinsulinemia underlie the metabolic syndrome, however it is incompletely understood how insulin regulates TRL metabolism. Moreover, TRLs are associated with increased cardiovascular risk, but the mechanisms by which TRLs affect atherosclerosis are not fully known. FoxOs are insulin-repressible transcription factors that have emerged as key mediators of insulin signaling in liver. We?ve determined that FoxOs regulate TRL metabolism, and in this grant, we will determine the mechanisms of this pathway. We will also investigate the effects of this pathway on atherosclerosis. Our study will rely on lipoprotein turnover in vivo using kinetic studies with radiolabeled tracers, and we will use genetic rescue approaches to test causative mechanisms. We will examine effects of the hepatic FoxO-TRL pathway on atherosclerosis and macrophage dysfunctions. These studies will shed light on key unanswered questions in the pathophysiology of metabolic syndrome-related cardiovascular risk, and may reveal better approaches for therapeutic intervention.
Diabetes and the metabolic syndrome are major risk factors for cardiovascular disease, which is the leading cause of death in the United States. Impairments in lipoprotein metabolism may link these disorders, but the mechanisms remain unclear. Identifying the key players in the relationships between metabolic syndrome, lipid metabolism, and atherosclerosis, will improve our ability to treat patients more effectively.
|Haeusler, Rebecca A; McGraw, Timothy E; Accili, Domenico (2018) Biochemical and cellular properties of insulin receptor signalling. Nat Rev Mol Cell Biol 19:31-44|
|Kim, KyeongJin; Goldberg, Ira J; Graham, Mark J et al. (2018) ?-Secretase Inhibition Lowers Plasma Triglyceride-Rich Lipoproteins by Stabilizing the LDL Receptor. Cell Metab 27:816-827.e4|
|Higuchi, Sei; Izquierdo, M Concepción; Haeusler, Rebecca A (2018) Unexplained reciprocal regulation of diabetes and lipoproteins. Curr Opin Lipidol 29:186-193|
|Lee, Samuel X; Heine, Markus; Schlein, Christian et al. (2018) FoxO transcription factors are required for hepatic HDL cholesterol clearance. J Clin Invest 128:1615-1626|
|Bertaggia, Enrico; Jensen, Kristian K; Castro-Perez, Jose et al. (2017) Cyp8b1 ablation prevents Western diet-induced weight gain and hepatic steatosis because of impaired fat absorption. Am J Physiol Endocrinol Metab 313:E121-E133|
|Langlet, Fanny; Haeusler, Rebecca A; Lindén, Daniel et al. (2017) Selective Inhibition of FOXO1 Activator/Repressor Balance Modulates Hepatic Glucose Handling. Cell 171:824-835.e18|
|Haeusler, Rebecca A; Camastra, Stefania; Nannipieri, Monica et al. (2016) Increased Bile Acid Synthesis and Impaired Bile Acid Transport in Human Obesity. J Clin Endocrinol Metab 101:1935-44|
|Ferrannini, Ele; Camastra, Stefania; Astiarraga, Brenno et al. (2015) Increased Bile Acid Synthesis and Deconjugation After Biliopancreatic Diversion. Diabetes 64:3377-85|