Multi-omics strategies define a new regulatory node in cardiometabolic disease pathogenesis
Dr. Christopher B. Newgard
Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC USA;
Abstract
We use multi-omics technologies to investigate metabolic regulatory mechanisms underlying development of cardiometabolic disease phenotypes. Our work has identified a metabolomic signature of perturbed branched chain amino acid (BCAA) catabolism that is associated with cardiometabolic diseases, predictive of intervention outcomes, and highly responsive to the most efficacious interventions for obesity and diabetes. BCAA restriction in Zucker fatty rats (ZFR) improves insulin sensitivity, and tissue metabolic profiling demonstrates that relief of mitochondrial fuel overload serves as a contributing mechanism for this effect. Metabolic flux analysis (“fluxomics”) demonstrates dynamic reciprocal regulation of tissue glycine levels in response to changes in BCAA, serving to relieve muscle nitrogen burden and export incompletely oxidized acyl CoAs out of muscle tissue in the form of glycine adducts. To investigate the impact of manipulation of BCAA catabolism, we have used small molecule inhibition of the kinase (BDK) or overexpression of the phosphatase (PPM1K) that regulate activity of the branched-chain ketoacid dehydrogenase (BCKDH) complex. Manipulation of BDK or PPM1K to activate BCKDH improves glucose, lipid and amino acid homeostasis in ZFR, including enhancement of insulin sensitivity and lowering of liver triglycerides. Phosphoproteomic analysis identified ATP-citrate lyase (ACL) as an alternative BDK/PPM1K substrate. Overexpression of BDK is sufficient to phosphorylate and activate ACL, leading to increased hepatic de novo lipogenesis. Finally, transcriptiomic profiling reveals that BDK is upregulated and PPM1K downregulated by fructose feeding and the ChREBP- transcription factor. These studies identify a new ChREBP-regulated mechanism that links BCAA, glucose and lipid metabolism. Manipulation of this node reverses several obesity-associated metabolic disease phenotypes.
Reference: White, P. and Newgard, CB. 2019. Branched-chain amino acids in disease. Science 363: 882-583.
Date： Sep 18, 2019 (Wed) 17:00—18:30
Place： Faculty of Science Bldg.3, 4F, room 412
Host： Shinya Kuroda (skuroda AT bs.s.u-tokyo.ac.jp)