Excess synthesis and storage of triacylglycerol (TAG) underlie much of the pathophysiology of major chronic disorders, including obesity, hepatic steatosis, atherosclerosis, the metabolic syndrome, and diabetes. Non-alcoholic fatty liver disease is a frequent prelude to fibrosis, cirrhosis and hepatocellular carcinoma, and the presence of TAG droplets in liver is required for replication of viruses like hepatitis C. Our long term goal is to determine how the enzymes in the pathway of TAG synthesis contribute to hepatic fatty acid use and how lipid intermediates of the TAG pathway control hepatic pathologies. The pathway of TAG and phospholipid biosynthesis is initiated by the rate-limiting enzyme, glycerol-3-phosphate acyltransferase (GPAT). As many as four independent GPAT isoforms are expressed in every cell, but why are multiple isoforms needed? We hypothesize that, although each GPAT isoform can, in theory, initiate the entire pathway of glycerolipid synthesis, independent isoforms are required to direct fatty acids towards complex lipid synthesis or away from ?-oxidation, to alter the rate of TAG synthesis under differing physiological conditions, to adjust the fatty acid composition of phospholipids and TAG, and to regulate nutrient-mediated signaling cascades that involve mTOR, PPAR?, and protein kinase C. To investigate how enhanced TAG synthesis in liver and muscle links to insulin resistance;we will determine mechanism(s) that underlie the effects of glycerolipid products of GPAT isoforms on PPAR? target genes and on the insulin signaling pathway. We will also determine how GPAT4 functions in phospholipid synthesis and energy metabolism by studying Gpat4-/- mice. These mice exhibit poor growth, are metabolically inefficient, have abnormal kinetics of dietary lipid absorption, and show increased energy expenditure despite decreased activity. These studies, using unique mouse models and innovative approaches, will address major gaps in our understanding of why excess tissue TAG is intimately associated with insulin resistance.
This project will enhance our understanding of non-alcoholic fatty liver disease, fatty heart disease, and the metabolic syndrome by a) examining how the enzymes that initiate triglyceride (fat) synthesis direct fatty acids towards different downstream pathways and b) investigating the metabolites that link obesity, triglyceride synthesis, and signaling pathways that alter the liver's response to insulin and other hormones.
|Pascual, Florencia; Coleman, Rosalind A (2016) Fuel availability and fate in cardiac metabolism: A tale of two substrates. Biochim Biophys Acta 1860:1425-33|
|Garcia-Fabiani, Maria B; Montanaro, Mauro A; Lacunza, Ezequiel et al. (2015) Methylation of the Gpat2 promoter regulates transient expression during mouse spermatogenesis. Biochem J 471:211-20|
|Cooper, Daniel E; Grevengoed, Trisha J; Klett, Eric L et al. (2015) Glycerol-3-phosphate Acyltransferase Isoform-4 (GPAT4) Limits Oxidation of Exogenous Fatty Acids in Brown Adipocytes. J Biol Chem 290:15112-20|
|Cooper, Daniel E; Young, Pamela A; Klett, Eric L et al. (2015) Physiological Consequences of Compartmentalized Acyl-CoA Metabolism. J Biol Chem 290:20023-31|
|Zhang, Chongben; Hwarng, Gwen; Cooper, Daniel E et al. (2015) Inhibited insulin signaling in mouse hepatocytes is associated with increased phosphatidic acid but not diacylglycerol. J Biol Chem 290:3519-28|
|Zhang, Chongben; Cooper, Daniel E; Grevengoed, Trisha J et al. (2014) Glycerol-3-phosphate acyltransferase-4-deficient mice are protected from diet-induced insulin resistance by the enhanced association of mTOR and rictor. Am J Physiol Endocrinol Metab 307:E305-15|
|Liu, Yong; He, Yizhou; Jin, Aiwen et al. (2014) Ribosomal protein-Mdm2-p53 pathway coordinates nutrient stress with lipid metabolism by regulating MCD and promoting fatty acid oxidation. Proc Natl Acad Sci U S A 111:E2414-22|
|Pellon-Maison, Magali; Montanaro, Mauro A; Lacunza, Ezequiel et al. (2014) Glycerol-3-phosphate acyltranferase-2 behaves as a cancer testis gene and promotes growth and tumorigenicity of the breast cancer MDA-MB-231 cell line. PLoS One 9:e100896|
|Zhang, Chongben; Klett, Eric L; Coleman, Rosalind A (2013) Lipid signals and insulin resistance. Clin Lipidol 8:659-667|
|Wilfling, Florian; Wang, Huajin; Haas, Joel T et al. (2013) Triacylglycerol synthesis enzymes mediate lipid droplet growth by relocalizing from the ER to lipid droplets. Dev Cell 24:384-99|
Showing the most recent 10 out of 54 publications