Our long-term research interests focus on two fundamental yet emerging areas in cell and medical biology:
1. Intracellular lipid (e.g., cholesterol and phosphatidylserine) sorting/transport, and its role in cancer, heart and neurodegenerative diseases.
2. The biogenesis and dynamics of lipid droplets, adipocyte development, obesity and diabetes.
These two areas are closely linked because lipid droplets may play a crucial role in cellular lipid transport, and lipid droplets are a primary storage site for both free and esterified cholesterol.
Cellular lipid trafficking is a difficult subject to study given the lack of effective approaches to label lipids in live cells. However, it is an important cell biological question because lipids are actively sorted and transported in all eukaryotic cells. In addition, many human diseases such as atherosclerosis, Alzheimer’s and cancer are linked to aberrant lipid transport.
My early work led to the identification of two key enzymes that catalyze sterol esterification, an important homeostatic step for storing excess sterols (Yang et al., Science, 1996). Our laboratory subsequently identified novel molecules and schemes that govern cellular lipid transport (Wang et al., EMBO J, 2005; Du et al, J Cell Biol., 2011; Ghai et al, Nature Communications, 2017; Dong et al., Nat Comms, 2019; Wang et al., Molecular Cell, 2019; Du et al., JCB, 2020; Qian et al., Cell, 2020). Currently we aim to identify and characterize novel proteins that regulate the trafficking of cholesterol or phosphatidylserine between cellular organelles.
Lipid droplets are key cellular organelles that regulate energy storage and metabolism. We have identified a number of factors that impact the size of lipid droplets (Fei et al, J Cell Biol., 2008; Fei et al, PLoS Genetics, 2011). One such protein, seipin, also plays an important role in human adipocyte development and maintenance (Cui et al., Human Mol Gen., 2011; Liu et al, Diabetes, 2014; Pagac et al, Cell Reports, 2016; Yan et al, Developmental Cell, 2018). Currently, we aim to understand how lipid droplets are formed from the ER and the exact role of seipin in this process.
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(1):6877. doi: 10.1038/s41467-021-27279-4.
Li YE, 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. Highlighted by Faculty Opinions https://facultyopinions.com/prime/740025624#tab=recommendations
Yan R., Cao P., Song W., Qian H., Du X., Coates H.W., Zhao X., Li Y., Gao S., Gong X., Liu X., Sui J., Lei J., Yang H., Brown A.J., Zhou Q., Yan C. and Yan N. (2021) A structure of human Scap bound to Insig-2 suggests how their interaction is regulated by sterols. SCIENCE, 371(6533):eabb2224. doi:10.1126/science.abb2224.
Du X. and Yang H. (2021) Seipin regulates the formation of nuclear lipid droplets from a distance. Journal of Cell Biology; 220 (1): e202011166.
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.
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.
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. Highlighted by JCB
Qian H., Zhao X., Yan R., Gao S., Sun X., Du X., Yang H., Wong CCL. and Yan N. (2020) Structural basis for catalysis and substrate specificity of human ACAT1. NATURE, 581: 333-338.
Luo J., Yang H. and Song B.L. (2020) Mechanisms and Regulation of Cholesterol Homeostasis. Nature Reviews Molecular Cell Biology. 21(4): 225-245.
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. Cover Story. Highlighted by Nature Reviews
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. published online July 24th.
Dong J., Du X., Wang H., Wang J., Lu C., Chen X., Zhu Z., Luo Z., Yu L., Brown A.J., Yang H* and Wu JW*. (2019) Allosteric enhancement of ORP1-mediated cholesterol transport by PI(4,5)P2/PI(3,4)P2. Nature Communications, 10: 829. * co-corresponding authors.
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. Journal of Biological Chemistry, 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. Journal of Biological Chemistry, 294, 1-16; doi:10.1074/jbc.RA119.009992
Gao M. and Yang H. (2018) VPS13: A lipid transfer protein making contacts at multiple cellular locations. Journal of Cell Biology, 217: 3322-3324.
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. Highlighted by F1000Prime
Du X, Zadoorian A, Lukmantara I, Qi Y, Brown AJ & Yang H. (2018) Oxysterol-binding protein-related protein 5 (ORP5) promotes cell proliferation by activation of mTORC1 signaling. Journal of Biological Chemistry, 293: 3806-3818.
Du X, Turner N & Yang H. (2018) The role of oxysterol binding proteins in cancer. Seminars in Cell and Developmental Biology, 81: 149-153.
Ghai R, Du X, Wang H, Dong J, Ferguson C, Brown AJ, Parton RG, Wu JW & Yang H. (2017) ORP5 and ORP8 bind phosphatidylinositol-4, 5-biphosphate (PtdIns(4,5)P2) and regulate its level at the plasma membrane. Nature Communications, 8:757. Highlighted by F1000Prime
Qi Y, Kapterian TS, Du X, Ma Q, Fei W, Zhang Y, Huang X, Dawes IW & Yang H. (2016). CDP-diacylglycerol synthases regulate the growth of lipid droplets and adipocyte development. Journal of Lipid Research, 57:767-80.
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 & 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.
Chu BB, Liao YC, Qi W, Xie C, Du X, Wang J, Yang H, Miao HH, Li BL & Song BL. (2015) Cholesterol transport through a lysosome-peroxisome membrane contact. CELL, 161: 291-306.
Du X, Brown AJ & Yang H. (2015). Novel mechanisms of intracellular cholesterol transport: membrane contact sites and oxysterol binding proteins. Current Opinion in Cell Biology, 35; 37-42.
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 & Yang H. (2014) Adipose-specific knockout of seipin/BSCL2 results in progressive lipodystrophy. Diabetes, 63:1–12 doi 10.2337/db13-0729
Du X, Kazim AS, Dawes IW, Brown AJ & Yang H. (2013) The AAA ATPase VPS4/SKD1 Regulates Endosomal Cholesterol Trafficking Independently of ESCRT-III. Traffic, 14: 107-19.
Yang H*, Galea A, Sytnyk V & Crossley M. (2012) Controlling the size of lipid droplets: protein and lipid factors. Current Opinion in Cell Biology, 24:509-16. (* corresponding author)
Cui X, Wang Y, Meng L, Fei W, Deng J, Xu G, Peng X, Ju S, Liu G, Zhao L & Yang H. (2012) Overexpression of a short isoform of human seipin/BSCL2 in mouse adipose tissue results in mild lipodystrophy. Am J Physiol Endocrinol Metab, 302: E705-13.
Du X, Kazim A, Brown AJ & 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. Highlighted by F1000Prime
Cui X, Wang Y, Tang Y, Liu Y, Zhao L, Deng J, Xu G, Peng X, Ju S, Liu, G & Yang H. (2011) Seipin ablation in mice results in severe generalized lipodystrophy. Human Molecular Genetics, 20: 3022-30
Fei W, Du X & Yang H. (2011) Seipin, adipogenesis and lipid droplets. Trends in Endocrinology and Metabolism, 22: 204-10.
Du X, Kumar J, Ferguson C, Schulz TA, Ong YS, Hong W, Prinz WA, Parton RG, Brown AJ & Yang H. (2011) A role for oxysterol-binding protein-related protein 5 in endosomal cholesterol trafficking. Journal of Cell Biology, 192: 121-135.
Fei W, Wang H, Fu X, Bielby C & Yang H. (2009) Conditions of endoplasmic reticulum stress stimulate lipid droplet formation in Saccharomyces cerevisiae. Biochemical Journal 424:61-7.
Low CP, Shui GH, Liew LP, Buttner S, Madeo F, Dawes IW, Wenk MR & Yang H. (2008) Caspase-dependent and -independent lipotoxic cell-death pathways in fission yeast. Journal of Cell Science, 121: 2671-2684. Editorial highlight by JCS
Fei W, Shui G, Gaeta B, Du X, Kuerschner L, Li P, Brown AJ, Wenk MR, Parton RG & Yang H. (2008) Fld1p, a functional homologue of human seipin, regulates the size of lipid droplets in yeast. Journal of Cell Biology, 180: 473-482. Highlighted by BioCentury Science Business Xchange
Yang H. (2006) Nonvesicular sterol transport: two protein families and a sterol sensor? Trends Cell Biol. 16: 427-32. Epub 2006 Jul 28.
Wang P, Zhang Y, Li H, Chieu HK, Munn AL & Yang H. (2005) AAA ATPases regulate membrane association of yeast oxysterol binding proteins and cellular sterol metabolism. EMBO Journal, 24: 2989-99
Zhang Q, Chieu HK, Low CP, Zhang S, Heng CK & Yang H. (2003) Schizosaccharomyces pombe cells deficient in triacylglycerols synthesis undergo apoptosis upon entry into the stationary phase. Journal of Biological Chemistry, 278: 47145-55
Yang H, Bard M, Bruner DA, Gleeson A, Deckelbaum RJ, Aljinovic G, Pohl T, Rothstein R & Sturley SL. (1996) Sterol Esterification in Yeast: A two gene process. Science, 272, 1353-1356.