Obesity and associated diseases, such as diabetes and hepatic steatosis, are characterized by excessive amounts of triglycerides (TGs) in tissues. To develop therapies for these diseases, an understanding of the molecular processes involved in the synthesis and storage of TGs is crucial. However, our understanding of the molecular and physiological aspects of TG metabolism is incomplete. The final and only committed step in triglyceride synthesis is catalyzed by acyl CoA:diacylglycerol acyltransferase (DGAT) enzymes. Mammals possess two DGAT enzymes, DGAT1 and DGAT2, which differ substantially in their biochemical and physiological functions. The current proposal addresses fundamental questions about DGAT enzymes at the biochemical, cellular, and physiological levels by pursuing three specific aims.
Aim 1 focuses on elucidating the posttranslational regulation of DGAT1 by phosphorylation.
Aim 2 focuses on elucidating physiological functions of DGAT1 by using murine genetic models with inactivation of the enzyme in specific tissues or cells relevant to fat metabolism, such as the adipose tissue, small intestine, and macrophages.
Aim 3 investigates an intriguing idea of manipulating DGAT expression in induced pluripotent stem (iPS) cells as a potential therapy for type 2 diabetes associated with obesity. Work resulting from these aims will advance the field of lipid synthesis as it relates to obesity. Because both DGAT enzymes are prospective targets of pharmaceutical approaches to treat obesity, diabetes, and hepatic steatosis, our studies also may have significant impact on the treatment of these diseases.
Obesity and related diseases, such as diabetes, occur when there is an overload of triglycerides in the fat and other tissues. This grant focuses on studying all aspects of the basic biology of the enzymes (called DGATs) that make triglycerides. Since DGAT enzymes are drug targets for treating or preventing obesity, diabetes, and related disorders of triglyceride metabolism, these studies are of great relevance to human health.
| Walther, Tobias C; Chung, Jeeyun; Farese Jr, Robert V (2017) Lipid Droplet Biogenesis. Annu Rev Cell Dev Biol 33:491-510 |
| Gluchowski, Nina L; Chitraju, Chandramohan; Picoraro, Joseph A et al. (2017) Identification and characterization of a novel DGAT1 missense mutation associated with congenital diarrhea. J Lipid Res 58:1230-1237 |
| Gluchowski, Nina L; Becuwe, Michel; Walther, Tobias C et al. (2017) Lipid droplets and liver disease: from basic biology to clinical implications. Nat Rev Gastroenterol Hepatol 14:343-355 |
| Chitraju, Chandramohan; Mejhert, Niklas; Haas, Joel T et al. (2017) Triglyceride Synthesis by DGAT1 Protects Adipocytes from Lipid-Induced ER Stress during Lipolysis. Cell Metab 26:407-418.e3 |
| Mul, Joram D; Begg, Denovan P; Haller, April M et al. (2014) MGAT2 deficiency and vertical sleeve gastrectomy have independent metabolic effects in the mouse. Am J Physiol Endocrinol Metab 307:E1065-72 |
| Krahmer, Natalie; Farese Jr, Robert V; Walther, Tobias C (2013) Balancing the fat: lipid droplets and human disease. EMBO Mol Med 5:973-83 |
| Shimazu, Tadahiro; Hirschey, Matthew D; Newman, John et al. (2013) Suppression of oxidative stress by ?-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339:211-4 |
| Klemm, Robin W; Norton, Justin P; Cole, Ronald A et al. (2013) A conserved role for atlastin GTPases in regulating lipid droplet size. Cell Rep 3:1465-75 |
| Currie, Erin; Schulze, Almut; Zechner, Rudolf et al. (2013) Cellular fatty acid metabolism and cancer. Cell Metab 18:153-61 |
| 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 44 publications
