Cellular Lipid and Energy Metabolism

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CTP:phosphocholine cytidylyltransferase (CCT) is the ratelimiting enzyme of phosphatidylcholine biosynthesis. CCT is localized to the surfaces of lipid droplets during their expansion. (A) Choline biosynthesis pathway. (B)  drosophila S2 cells cultured with oleic acid. CK, choline kinase. CPT, CDPcholine: diacylglycerol cholinephosphotransferase. Bar, 1 μm.

Because energy availability varies, living organisms need to store energy. This is done most efficiently as triacylglycerols (TGs). Within cells, TGs and other nonpolar lipids are stored in cytosolic lipid droplets (LDs). Excessive accumulation of lipids in LDs within tissues underlies the pathogenesis of diseases, such as obesity, diabetes, fatty liver and atherosclerosis. Additionally, lipid storage in LDs is a focus of efforts to increase oil yields from crops or microorganisms. An understanding of how cells synthesize, store and utilize lipids is, therefore, of fundamental importance.

We study the mechanisms of cellular lipid synthesis and storage. Our studies range from the basic biology of diacylglycerol acyltransferases (DGATs) and other enzymes involved in TG synthesis to genetic models aimed at discovering genes that govern LD formation. Our model systems include yeast, mammalian cells, mice and human induced pluripotent stem (iPS) cells. Our discoveries of basic mechanisms from in vitro and cellular studies are tested in whole organisms for their applications to physiology and disease.

Together with Tobias Walther at Yale University, we recently identified a key mechanism involved in LD expansion. We found that growing LDs require specific phospholipids to coat their surfaces and that the synthesis of these lipids is activated at LD surfaces through a fascinating homeostatic mechanism. In recent physiological studies, we showed that mice overexpressing DGAT1 in macrophages, which leads to increased TG storage capacity, are protected against the detrimental consequences of obesity. In collaborative studies with the Ott laboratory, we identified DGAT1 as a host factor that is required for efficient infection of liver cells by the hepatitis C virus and that DGAT1 is required for the virus to induce hepatic steatosis.

Our laboratory also researches the basic mechanisms of frontotemporal dementia (FTD), the most common cause of dementia in people under age 65. As part of the Consortium for FTD Research, we use a variety of model systems to study the pathogenesis of FTD and search for cures. Recent advances include generating murine models of FTD with progranulin deficiency and showing that mice lacking progranulin are predisposed to neuroinflammation, generating and studying iPS cells from FTD patients and establishing yeast models for studying the role of the protein TDP43 in FTD pathogenesis.

 Recent Publications

Farese, RV Jr, Walther TC. Cell biology of lipid  droplets. Annu. Rev. Biochem. In press.

Harris C et al. (2011) The hepatitis C virus core protein decreases lipid droplet turnover: A mechanism for core-induced steatosis. J. Biol. Chem. 286:42615–42625.

Herker E et al. (2010) Hepatitis C virus particle formation requires diacyglycerol acyltransferase (DGAT1). Nat. Med. 16:1295–1298.

Koliwad SK et al. (2010) Increased capacity for triacylglycerol synthesis in macrophages protects mice from metabolic consequences of diet induced obesity. J. Clin. Invest. 120:756–767.

Krahmer N et al. (2011) Phosphatidylcholine synthesis for lipid droplet expansion is mediated by localized activation of CTP:phosphocholine  cytidylyltransferase. Cell Metab. 14:504–515.