- Columbia University, New York City, NY, 1998
Areas of Interest
The primary goal of my laboratory is to understand the molecular mechanisms governing the sorting, trafficking, and storage of cellular lipids in health and disease. A major direction has been to define how lipid droplets originate and grow from the endoplasmic reticulum. Lipid droplets store triacylglycerols and cholesteryl esters and play important roles in cell biology and physiology. However, the mechanisms governing their biogenesis and growth remain incompletely understood. My group identified several key proteins that regulate lipid droplet formation, including seipin, AGPAT2, ORP5 and DFCP1 etc. Seipin has now become one of the most relevant protein to the biogenesis of lipid droplets. Importantly, both seipin and AGPAT2 are essential to adipogenesis, as null mutations in the seipin or AGPAT2 gene cause severe congenital generalized lipodystrophy in humans. Thus, the biogenesis of lipid droplets in a cell is intimately linked to the formation and maintenance of adipose tissue. An ongoing effort in my laboratory is to elucidate the molecular mechanisms underlying lipid droplet formation and to understand how lipid droplet formation may impact the structure and function of adipose tissue. Our work in this area has generated new insights into the storage of lipids at both cellular and systemic levels.
Another major direction has been to investigate how lipids are sorted and transported in mammalian cells. Lipid distribution is highly uneven among organellar membranes. How mammalian cells maintain distinct lipid composition for each organellar membrane remains a fundamental question in biology. My group identified ORP2 as a key protein that delivers cholesterol to the plasma membrane where most cellular cholesterol resides. My group also identified TMEM41B and VMP1 as novel scramblases of the endoplasmic reticulum. Our work along this direction has generated new insights into how cells regulate the distribution of key lipids such as cholesterol and phosphatidylserine. Our current effort focuses on the physiological and pathological consequences of dysregulated lipid distribution.
Overall, our work has important implications for obesity, diabetes, cancer, cardiovascular and neurogenerative diseases. Based on original discoveries made by our group, new compounds which may be used to treat cancer and neurodegenerative disorders are being developed.
Visit the PubMed profile page
- Zadoorian A., Du X. and Yang H. (2023). Lipid droplet biogenesis and functions in health and disease. Nature Reviews Endocrinology, 19: 443-459. doi: 10.1038/s41574-023-00845-0
- Lukmantara I, Chen F, Mak HY, Zadoorian A, Du X, Xiao FN, Norris DM, Pandzic E, Whan R, Zhong Q and Yang H. (2022). PI(3)P and DFCP1 regulate the biogenesis of lipid droplets. Mol Biol Cell. 33(14):ar131.
- Mak HY, Ouyang Q, Tumanov S, Xu J, Rong P, Dong F, Lam SM, Wang X, Lukmantara I, Du X, Gao M, Brown AJ, Gong X, Shui G, Stocker R, Huang X, Chen S and Yang H. (2021). AGPAT2 interaction with CDP-diacylglycerol synthases promotes the flux of fatty acids through the CDP-diacylglycerol pathway. Nature Communications. 12: 6877.
- Li EY, Wang Y, Du X, Zhang T, Mak HY, Hancock SE, McEwen H, Pandzic E, Whan RM, Aw YC, Lukmantara IE, Yuan Y, Dong X, Don A, Turner N, Qi S, and Yang H. (2021). TMEM41B and VMP1 are scramblases and regulate the distribution of cholesterol and phosphatidylserine. Journal of Cell Biology, 220(6): e202103105.
- Du X., Zhou L., Aw Y.C., Mak H.Y., Xu Y., Rae J., Wang W., Zadoorian A., Hancock S.E., Osborne B., Chen X., Wu J.W., Turner N., Parton R.G., Li P. and Yang H. (2020). ORP5 Localizes to ER-Lipid Droplet Contacts and Regulates the Level of PI(4)P on Lipid Droplets. Journal of Cell Biology. 219, 1-16.
- Gao M., Liu L., Wang X., Mak H.Y., Liu G. and Yang H. (2020). GPAT3 deficiency alleviates insulin resistance and hepatic steatosis in a mouse model of severe congenital generalized lipodystrophy. Human Molecular Genetics. 1; 29: 432-443.
- Qian H., Wu X., Du X., Yao X., Zhao X., Lee J., Yang H.* and Yan N*. (2020). Structural basis of low pH-dependent lysosomal cholesterol egress by NPC1 and NPC2. Cell, 182: 1-14. * Co-corresponding authors.
- Wang H., Ma, Q., Qi, Y., Dong, J., Du, X., Rae, J., Brown A.J., Parton R.G., Wu J.W. and Yang H. (2019). ORP2 delivers cholesterol to the plasma membrane in exchange for phosphatidylinositol 4, 5-bisphosphate (PI(4,5)P2). Molecular Cell. 73, 1–16.
- Xu Y., Du X., Turner N., Brown AJ and Yang H. (2019). Enhanced acyl-CoA: cholesterol acyltransferase activity increases cholesterol levels on lipid droplet surface and impairs adipocyte function. J. Biol. Chem. 294: 19306-19321.
- Xu Y., Mak H.Y., Lukmantara I., Li Y.E., Hoehn K.L., Huang X., Du X. and Yang H. (2019). CDP-DAG Synthase 1 and 2 regulate lipid droplet growth through distinct mechanisms. J. Biol. Chem. 294: 16740-16755.
- Gao M., Huang X., Song B.L. and Yang H. (2019). The biogenesis of lipid droplets: lipids take center stage. Progress in Lipid Research, 75:100989.
- Yan R., Qian H., Lukmantara I., Gao M., Du, X., Yan N. and Yang H. (2018). Human SEIPIN Binds Anionic Phospholipids. Developmental Cell, 47, 1–9
- Du X., Zadoorian A., Lukmantara I., Qi Y., Brown A.J. and Yang H. (2018). Oxysterol-binding protein-related protein 5 (ORP5) promotes cell proliferation by activation of mTORC1 signalling. J. Biol. Chem. 293: 3806-3818.
- Ghai R, Du X, Wang H, Dong J, Ferguson C, Brown AJ, Parton RG, Wu JW and Yang H. (2017). ORP5 and ORP8 bind phosphatidylinositol-4, 5-bisphosphate (PtdIns(4,5)P2) and regulate its level at the plasma membrane. Nature Communications, 8: 757
- Pagac M, Cooper DE, Qi Y, Lukmantara IE, Mak HY, Wu Z, Tian Y, Liu Z, Lei M, Du X, Ferguson C, Kotevski D, Sadowski P, Chen W, Boroda S, Harris TE, Liu G, Parton RG, Huang X, Coleman RA and Yang H. (2016). SEIPIN regulates lipid droplet expansion and adipocyte development through modulating the activity of glycerol-3-phosphate acyltransferase. Cell Reports, 17, 1546–1559.
- Liu L, Jiang QQ, Wang, X, Zhang Y, Lin RC, Lan S, Shui, G, Zhou L, Li P, Wang Y, Cui X, Gao MM, Zhang L, Lv Y, Xu G, Liu G, Zhao D and Yang H. (2014). Adipose-specific knockout of seipin/BSCL2 results in progressive lipodystrophy. Diabetes. 63:1–12
- Du X, Kazim A, Brown AJ and Yang H. (2012). An essential role of Hrs/Vps27 in endosomal cholesterol trafficking. Cell Reports, 1: 29-35. (Inaugural Issue).
- Fei W, Shui G, Zhang Y, Krahmer N, Ferguson C, Kapterian TS, Lin RC, Dawes IW, Brown AJ, Li P, Huang X, Parton RG, Wenk MR, Walther TC, Yang H (2011). A role for phosphatidic acid in the formation of “supersized” lipid droplets. PLoS Genetics, 7: e1002201.
- Fei W, Shui G, Gaeta B, Du X, Kuerschner L, Li P, Brown AJ, Wenk MR, Parton RG and Yang (2008). Fld1p, a functional homologue of human seipin, regulates the size of lipid droplets in yeast. J. Cell Biol.180: 473-482.
- Yang, H., Bard, M., Bruner, D. A., Gleeson, A., Deckelbaum, R. J., Aljinovic, G., Pohl, T., Rothstein, R., and Sturley, S. L. (1996). Sterol Esterification in Yeast: A two gene process. Science 272, 1353-1356.