Yuguang ‘Roger’ Shi, PhD

Research

My research work focuses on translational aspects of type 2 diabetes and other aging-related metabolic diseases, from identification and validation of novel drug targets, development of high throughput screening assays, to preclinical testing of potential therapeutic compounds in animal models. Our work has recently identified a critical missing link between mitochondrial dysfunction in aging and the onset aging-related metabolic diseases, including diabetes, heart failure, stroke, and Alzheimer’s diseases. Using genome-wide synthetic lethal screening, we have also identified a family of novel regulators of phospholipid trafficking between ER and mitochondria. We are currently characterizing their function in regulating the onset of aging-related diseases.

Related Diseases: Mitochondrial dysfunction, cardiolipin remodeling, aging, metabolic diseases.

Techniques: Molecular cloning, confocal imaging analysis of mitochondrial dynamics, enzymatic assays, signal transduction, mitochondrial respiration, transgenic and knockout mice, metabolic phenotyping, echocardiography, glucose tolerance, insulin tolerance and animal surgery.

Awards & Accomplishments

Major Achievements in Research

1. Groundbreaking work on the identification of ALCAT1 as the missing link between aging and aging-related diseases. Aging is the primary cause for a family of age-related chronic diseases, including type 2 diabetes, cardiovascular disease, neurogenerative diseases, and cancer. However, the underlying causes for these conditions remains poorly understood, which prevents the development of effective treatment for these disorders. Our groundbreaking work on ALCAT1 has identified the enzyme as one of the root causes for aging that links aging with the onset of various ageing-related diseases. My lab pioneered the cloning and characterization of ALCAT1, the first acyl-CoA:lysocardiolipin acyltransferase and the first phospholipid remodeling enzyme. My research work during the last 15 years demonstrates that upregulation of ALCAT1 by oxidative stress links aging with the development of all the aging-related diseases by catalyzing pathological remodeling of cardiolipin. Cardiolipin (CL) is a mitochondrial signature phospholipid that is required for mitochondrial membrane structure, dynamics, biogenesis, mitophagy, apoptosis, and inflammation. We and others have previously shown that the onset of aging and aging-related diseases causes pathological remodeling of CL by polyunsaturated fatty acids (PUFA). Enrichment of PUFA renders CL highly sensitive to oxidative damage by reactive oxygen species (ROS), leading to CL depletion, mitochondrial DNA (mtDNA) release and mitochondrial dysfunction. We also identified ALCAT1 as the key enzyme that catalyzes the pathological remodeling of CL in various aging-related diseases.

My work at the Barshop Aging Institute and Penn State University College of Medicine has demonstrated that ALCAT1 deficiency not only significantly extends lifespan, but also prevents the onset of a whole family of aging-related chronic diseases, including premature aging caused by mutation of mitochondrial DNA polymerase (PolG) or telomerase shortening, type 2 diabetes, diabetic complications (retinopathy, cardiomyopathy, and nephropathy), heart diseases (coronary artery, heart failure caused by transaortic constriction, angiotensin-induced cardiomyopathy, doxorubicin-induced heart failure), pulmonary hypertension, Parkinson’s disease, Alzheimer’s disease, and cancer caused by whole-body deletion of the p53 gene. Together, our work has identified ALCAT1 as one of the root causes of aging and aging-related diseases, and have validated the enzyme as a novel drug target for these disorders. The majority of our research work remains to be published (more than 10 manuscripts in preparation).

2. Translational research on ALCAT1 as a novel drug target for aging and aging-related diseases. Using Dafaglitapin (Dafa), a novel, potent, and highly selective ALCAT1 inhibitor co-developed between my lab at Penn State University and a biotech company, we have validated ALCAT1 as a novel drug target for aging-related chronic diseases. Our work shows that treatment of mice with Dafa successfully mitigated a whole family of chronic diseases, including diabetic complications (retinopathy, cardiomyopathy, and nephropathy), Parkinson’s disease, Alzheimer’s disease, non-small cell lung cancer, cancer induced by p53 deletion, and heart failure induced by doxorubicin, hypoxia, coronary artery ligation, transaortic constriction, and pulmonary hypertension. Our findings provide proof of concept studies that targeting ALCAT1 with small molecule inhibitors will provide a first-in-class treatment of these devastating diseases, and therefore will likely have a huge impact in the field if proven in human clinical trials in the future.

3. Validation of ALCAT1 as a novel drug target for the treatment of Barth syndrome. Barth syndrome (BTHS) is an X-linked genetic disorder caused by mutations in the tafazzin (TAZ) gene. TAZ encodes a mitochondrial transacylase that catalyzes the remodeling of CL with linoleolic acid. CL is a mitochondrial phospholipid enriched in the heart, and plays a key role in maintaining cardiac function. This functional importance is determined by the acyl composition of CL. In the healthy mammalian heart, the four fatty acyl chains of CL are dominated by linoleic acid (C18:2), also known as tetralinoleoyl CL (TLCL). This unique structure is pivotal to cardiac function as it supports the optimum activity of numerous mitochondrial proteins and enzymes. Consequently, TAZ mutation in BTHS causes depletion of TLCL, leading to oxidative stress, mitochondrial dysfunction, dilated cardiomyopathy, and permature death of male teanagers. Unfortunately, there is no treatment for this lethal condition, because the underlying causes for the pathogenesis remains largely unknown.

Our research work over the last 10 years has identified ALCAT1 as a novel drug target for BTHS. We show that ALCAT1 expression is upregulated by BTHS, leading to pathological remodeling of CL with aberrant fatty acyl chains that are enriched with docosahexaenoic acid (C22: 6). This modification renders CL highly sensitive to oxidative damage by reactive oxygen species (ROS). Hence, overexpression of ALCAT1 in cultured cardiomyocytes leads to multiple metabolic defects that are reminiscent of those in BTHS, including TLCL depletion, oxidative stress, and mitochondrial dysfunction. Using mice with targeted deletion of ALCAT1, we further demonstrate that ablation of ALCAT1 prevents cardiomyopathy and left ventricular dysfunction in mice with inducible TAZ knockdown by restoring mitochondrial function. These exciting findings have provided key insights on targeting ALCAT1 with small molecule inhibitors for the treatment of this lethal condition. This work has been sponsored continuously by the Barth Syndrome Foundation for the last 10 years.

4. Identified LPGAT1 as a key regulator of MEGDEL syndrome. MEGDEL syndrome is an inherited disorder that affects multiple body systems. Defective remodeling of phosphatidylglycerol (PG), a mitochondrial signature phospholipid is implicated in the pathogenesis of the disease. However, the underlying cause for this defect remains elusive. LPGAT1 is the first acyltransferase that catalyzes the remodeling of phosphatidylglycerol (PG) initially identified by my lab. PG is a mitochondrial phospholipid required for the synthesis of cardiolipin (CL). We show that mice with targeted deletion of the LPGAT1 gene causes mitochondrial dysfunction, oxidative stress, and mtDNA depletion, leading to the development of MEGDEL syndrome, including hepatopathy, acidosis, hearing loss, cardiomyopathy and premature death from heart failure. Together, these findings identified LPGAT1 as one of the genes which when mutated causes MEGDEL syndrome.

5. Discovered Aster proteins as novel regulators of lysosomal activation of mTORC1 signaling and mitochondrial cholesterol transport. Nutrient sensing by the mTOR complex 1 (mTORC1) requires its translocation to the lysosomal membrane. Upon amino acids removal, mTORC1 becomes cytosolic and inactive, yet its precise subcellular localization and the mechanism of inhibition remain elusive. Here, we identified Aster-C as a negative regulator of mTORC1 signaling. Aster-C earmarked a special rough ER subdomain where it sequestered mTOR together with the GATOR2 complex to prevent mTORC1 activation during nutrient starvation. Amino acids stimulated rapid disassociation of mTORC1 from Aster-C concurrently with assembly of COP I vesicles which escorted mTORC1 to the lysosomal membrane. Consequently, ablation of Aster-C led to spontaneous activation of mTORC1 and dissociation of TSC2 from lysosomes, whereas inhibition of COP I vesicle biogenesis or actin dynamics prevented mTORC1 activation. Together, these findings identified Aster-C as a missing link between lysosomal trafficking and mTORC1 activation by revealing an unexpected role of COP I vesicles in mTORC1 signaling.

Cholesterol plays a pivotal role in mitochondrial steroidogenesis, membrane structure, and respiration. Mitochondrial membranes are intrinsically low in cholesterol content and therefore must be replenished with cholesterol from other subcellular membranes. However, the molecular mechanisms underlying mitochondrial cholesterol transport remains poorly understood. The Aster-B gene encodes a cholesterol binding protein recently implicated in cholesterol trafficking from the plasma membrane to the endoplasmic reticulum (ER). In this study, we investigated the function and underlying mechanism of Aster-B in mediating mitochondrial cholesterol transport. Ablation of Aster-B impaired cholesterol transport from the ER to mitochondria, leading to a significant decrease in mitochondrial cholesterol content. Aster-B is also required for mitochondrial transport of fatty acids derived from hydrolysis of cholesterol esters. A putative MTS at the N-terminus of Aster-B mediates the mitochondrial cholesterol uptake. Deletion of the MTS or ablation of Arf1 GTPase which is required for mitochondrial translocation of ER proteins prevented mitochondrial cholesterol transport, leading to mitochondrial dysfunction.

6. Developed a de novo lipid labeling method to monitor lipid trafficking in live cells. Lipids exert dynamic biological functions which are determined both by their fatty acyl compositions and precise spatiotemporal distributions inside the cell. However, it remains a daunting task to investigate any of these features in live cells for each of the more than 1000 lipid species in a typical mammalian cell. However, it remains a challenging issue in lipid research to specifically label individual lipid species in live cells. Here we resolved this issue by developing a de novo lipid labeling method for major lipid species, including glycerolipids, glycerophospholipids, and cholesterol esters by using a single fluorescent probe. The method not only allowed us to probe the precise subcellular distribution and trafficking of individual lipid species in live cells, but also uncovered some unexpected biological functions of previously reported lipid metabolic enzymes that were not possible by conventional biochemical methods. We envision that this method will become an indispensable tool for the functional analysis of individual lipid species and numerous lipid metabolic enzymes and transporters in live cells.

7. A paradigm shift discovery demonstrating that insulin resistance in skeletal muscle protects the heart in response to metabolic stress. Obesity and type 2 diabetes mellitus (T2DM) are the leading causes of cardiovascular morbidity and mortality. Although insulin resistance is believed to underlie these disorders, anecdotal evidence contradicts this common belief. Accordingly, obese patients with cardiovascular disease have better prognoses relative to leaner patients with the same diagnoses, whereas treatment of T2DM patients with thiazolidines, one of the popular insulin sensitizer drugs, significantly increases the risk of heart failure. Using mice with skeletal muscle-specific ablation of the insulin receptor gene (MIRKO), we addressed this paradox by demonstrating that insulin signaling in skeletal muscles specifically mediated crosstalk with the heart, but not other metabolic tissues, to prevent cardiac dysfunction in response to metabolic stress. Despite severe hyperinsulinemia and aggregating obesity, MIRKO mice were protected from myocardial insulin resistance, mitochondrial dysfunction, and metabolic reprogramming in response to diet-induced obesity (DIO). Consequently, the MIRKO mice were also protected from myocardial inflammation, cardiomyopathy, and left ventricle dysfunction. Together, our findings suggest that insulin resistance in skeletal muscle functions as a double-edged sword in metabolic diseases.

Publications

PUBLICATIONS (Selected):

1. Jia, D., Zhang, J., Liu, X., Andersen, J.P., Tian, Z. Nie, J. Shi*, Y. (2021) Insulin Resistance in Skeletal Muscle Selectively Protects the Heart in Response to Metabolic Stress. Diabetes (accepted).

2. Jia, D., Zhang, J., Nie, J. Andersen, J.P., Rendon, S., Zheng, Y., Liu, X.,Tian, Z, and Shi*, Y. (2021) Cardiolipin Remodeling by ALCAT1 Links Hypoxia to Coronary Artery Disease by Promoting Mitochondrial Dysfunction. Mol. Therap. (accepted with minor revision).

3. Andersen, J.P., Zhang, J., Sun, H., Liu, X., Liu, J. Nie, J. Shi*, Y. (2020) Aster-B Coordinates with Arf1 to Regulate Mitochondrial Cholesterol Transport. Mol. Metab. (Cover Story). 42:101055.

4. Zhang, J., Andersen, J.P., Sun, H., Nie, J., and Shi*, Y. (2020). Aster-C Coordinates with COP I Vesicles to Regulate Nutrient Sensing by mTORC1. EMBO Rep 3;21 (9):e49898.

5. Song, C., Zhang, J., Qi, S., Liu, Z., Zhang, X., Zheng, Y., Andersen, J.P., Zhang W.J., Strong, R., Martinez, A., Musi, N., Nie, J. and Shi*, Y. (2019). Cardiolipin Remodeling by ALCAT1 Links Mitochondrial Dysfunction to Parkinson’s Diseases Aging Cell 18(3):e12941.

6. Zhang, X., Zhang, J., Sun, H., Liu, X., Zheng, Y., Xu, D., Wang, J., Jia, D., Han, X., Liu, F., Nie, J., and Shi*, Y. (2019). Defective Phosphatidylglycerol Remodeling Causes Hepatopathy, Linking Mitochondrial Dysfunction to Hepatosteatosis. Cell. & Mol. Gastroenterol. & Hepatol (Cover Story). 7(4):763-781.

7. Nie, J., Sun, C., Liu, X., Chang, Z., Zhang, W., Zhai, Y., and Shi*, Y. (2018). Phosphorylation of GDIα at Ser174 by SAD-A Is Required for Glucose-stimulated Insulin Secretion from Pancreatic β-cells. Endocrinol. 159(8):3036-3047

8. Li, X., Thome, S., Ma, X., Amrute-Nayak, M., Finigan, A., Kitt, L., Masters, L., James, J.R., Shi, Y., Meng, G., and Mallat, Z. (2017). MARK4 Regulates NLRP3 Positioning and Inflammasome Activation through a Microtubule-dependent Mechanisms. Nat. Comm. 28;8:15986.

9. Shang, Y., He, J., Wang, Y., Feng, Q., Zhang, Y., Guo, J., Li, J., Li, S., Wang, Y., Yan, G., Ren, F., Shi, Y., Xu, J., Zeps, N., Zhai, Y., He, D., and Chang. Z. (2017) CHIP/Stub1 Regulates the Warburg Effect by Promoting Degradation of PKM2 in Ovarian Carcinoma. Oncogene 36, 4191-4200.

10. Liu, G., Zhou, L, Zhang, H., Chen, R., Zhang, Y., Li, L., Lu, J-Y., Jiang, H., Liu, D., Qi, S., Jiang, Y-M., Yin, K., Xie, Z., Shi, Y., Liu, Y., Cao, X., Chen, Y., Zou, D-Y., and Zhang, W.P. (2017). Regulation of Hepatic Lipogenesis by the Zinc Finger Protein ZBTB20. Nat. Commun. 8:14824.

11. Hsu, P. and Shi*, Y. (2016). Regulation of Autophagy by Mitochondrial Phospholipids in Health and Diseases. BBA – Mol. Cell Biol. Lipids 1862(1):114-129

12. Klionsky, D.J.…..Shi, Y., ……. Zughaier SM (2016). Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy. 12(1):1-222.

13. Cao D., Ma, X., Cai, J., Luan, J., Liu, A.J., Yang, R., Cao, Y., Zhu, X., Zhang, H., Chen, Y.X., Shi, Y., Shi, G.X., Zou, D., Cao, X., Grusby, M.J., Xie, Z., Zhang, W.J. (2016) ZBTB20 is required for anterior pituitary development and lactotrope specification. Nat Commun. 15;7:11121

14. Li, L., Gao, L., Wang, K., Ma, X., Chang, X., Shi, J-H., Zhang, Y., Yin, K., Liu, Z., Shi, Y., Xie, Z., Zhang, W.J. (2016) Knockin of Cre Gene at Ins2 Locus Reveals No Cre Activity in Mouse Hypothalamic Neurons. Sci Rep. 6:20438.

15. Liu, Y., Takahashi,Y., Desai, N., Zhang, J, Serfass, J.M., Shi Y., Lynch, C.J., and Wang, H.-G. (2016). Bif-1 deficiency impairs lipid homeostasis and causes obesity accompanied by insulin Resistance. Sci Rep. 6:20453.

16. Chen, F., Sha, M., Wang, Y., Wu, T., Shan, W., Liu, J., Zhou, W., Zhu, Y., Sun, Y., Shi, Y., Bleich, D., and Han, X. (2016). Transcription factor Ets-1 links glucotoxicity to pancreatic beta cell dysfunction through inhibiting PDX-1 expression in rodent models. Diabetologia. 59(2):316-24

17. Zhou, X., Jun, X., Shi, Y., & Ye, J.M. (2015). Discovery of novel anti-diabetic drugs by targeting lipid metabolism, Curr Drug Targets 16(12):1372-80.

18. Hsu, P., Liu, X., Zhang, J., and Shi*, Y. (2015). Cardiolipin Remodeling by Tafazzin Is Selectively Required for the Initiation of Mitophagy. Autophagy 11(4):643-52.

19. Wang, L., Liu, X., Nie, J., Zhang, J., Kimball, S.R., Zhang, H., Zhang, W., Jefferson, LS, Cheng, Z., Ji, Q., and Shi*, Y. (2015). Cardiolipin Remodeling by ALCAT1 Links Defective Mitophagy to Fatty Liver Diseases. Hepatology 61(2):486-96.

20. Zhang, J., Xu, D., Nie, J., Han, R., Zhai, Y., and Shi*, Y. (2014). Comparative Gene Identification-58 (CGI-58) Promotes Autophagy as a Putative Lysophosphatidylglycerol Acyltransferase. J. Biol. Chem. 289(47):33044-53.

21. Zhang, J., Xu, D., Nie, J., Cao, J., Zhai, Y., Tong, D., and Shi*, Y. (2014). Monoacylglycerol Acyltransferase-2 Is a Tetrameric Enzyme that Selectively Heterodimerizes with Diacylglycerol Acyltransferase-1. J. Biol. Chem. 289(15):10909-18.

22. Chen, S.J., Hoffman, N.E., Shanmughapriya, S, Bao, L., Keefer, K., Conrad, K., Merali, S., Takahashi, Y., Abraham, T., Hirschler-Laszkiewicz, I., Wang, J., Zhang, X.Q., Song, J., Barrero, C., Shi, Y., Kawasawa, Y.I., Bayerl, M., Sun, T., Barbour, M., Wang, H.G., Madesh, M., Cheung, J.Y., and Miller, B.A. (2014). A Splice Variant of the Human Ion Channel TRPM2-L Inhibits Mitochondrial Bioenergetics and Tumor Growth. J. Biol. Chem. 289(52):36284-302.

23. Nie, J., Han, X., Shi*, Y. (2013). SAD-A and AMPK Kinases: the “Yin and Yang” Regulators of mTORC1 Signaling in Pancreatic β-cells. Cell Cycle 12(21):3366-9

24. Nie, J., Liu, X., Kimball S. R., Zhang, J., Wang, L., Zhang, W., Jefferson, L.S., Han, X., and Shi*, Y. (2013). SAD-A Kinase Controls Islet β-Cell Size and Function as a Mediator of mTORC1 Signaling. Proc. Natl. Acad. Sci. USA. 110(34):13857-62

25. Zhu, Y., You, W., Wang, H., Li, Y., Qiao, N., Shi, Y., Zhang, C., Bleich D., and Han, X. (2013) MicroRNA-24/MODY Gene Regulatory Pathway Mediates Pancreatic β-Cell Dysfunction. Diabetes 62(9):3194-206.

26. Nie, J., Lilley, B.N., Pan, Y.A., Faruque, O., Liu, X., Sanes, J.R., Han, H., and Shi*, Y. (2013). SAD-A Potentiates Glucose-stimulated Insulin Secretion as a Mediator of GLP-1 Response in Pancreatic β-cells. Mol. Cell. Biol. 33(13):2527-34.

27. Sun, C., Tian L., Nie, J., Han, X., and Shi*, Y. (2012). Deletion of MARK4 kinase leads to hyperphagia, insulin hypersensitivity, and resistance to diet-induced obesity. J. Biol. Chem. 287(45):38305-15.

28. Liu, X., Ye, B., Miller, S., Yuan, H., Zhang, H., Tian, L., Nie, J., Imae, R., Arai, H., Li, Y., Cheng, Z., and Shi*, Y. (2012). Ablation of ALCAT1 mitigates hypertrophic cardiomyopathy through effects on oxidative stress and mitophagy. Mol. Cell. Biol. 32(21):4493-504.

29. Nie J, Sun C, Faruque O, Ye G, Li J, Liang Q, Chang Z, Yang W, Han X, Shi*Y. (2012) Synapses of amphids defective (SAD-A) kinase promotes glucose-stimulated insulin secretion through activation of p21-activated kinase (PAK1) in pancreatic β-cells. J. Biol. Chem. 287(31):26435-44.

30. Chen, D., Liu, X., Zhang, W., and Shi*, Y. (2012) Targeted Inactivation of GPR26 Leads to Hyperphagia and Adiposity by Activating AMPK in the Hypothalamus. PLoS One. 7(7):e40764

31. Li, J., Liu, X., Wang,H., Zhang, W., Chan, D.C., and Shi*, Y. (2012). Lysocardiolipin Acyltransferase-1 (ALCAT1) controls mitochondrial biogenesis and mtDNA fidelity through modulation of MFN2 expression. Proc. Natl. Acad. Sci. USA 109(18):6975-80.

32. Hao, X., Wang, Y., Ren, F., Zhu, S., Ren, Y., Jia, B., Y-P, Li, Shi, Y. and Chang, Z. (2011). SNX25 regulates TGF-β signaling by enhancing the receptor degradation. Cell Signal. 23(5):935-46.

33. Zhu, Y., Shu, T., Lin, Y., Wang, H., Yang ,J., Shi, Y., and Han X. (2011) Inhibition of the receptor for advanced glycation endproducts (RAGE) protects pancreatic β-cells. Biochem. Biophys. Res. Commun. 404(1):159-65.

34. Li, J., Romestaing, C., Han X., Li, Y., Hao, X., Wu Y., Sun, C., Jefferson, L. S., Xiong, J., LaNoue, K.F., Chang, Z., Lynch, C.J., Wang, H., and Shi*, Y. (2010) Cardiolipin Remodeling by ALCAT1 Links Oxidative Stress and Mitochondrial Dysfunction to Obesity. Cell Metab. 12, 154-165.

35. Shi*, Y. (2010) Emerging Roles of Cardiolipin Remodeling in Mitochondrial Dysfunction Associated with Diabetes, Obesity, and Cardiovascular Diseases. J. Biomed. Res. 24(1):6-15.

36. Nie, J., Hao, X., Chen, D., Han, X., Chang, Z., and Shi*, Y. (2009) A Novel Function of the Human CLS1 in Phosphatidylglycerol Synthesis and Remodeling. Biochim. Biophys. Acta-Mol. & Cell Biol. Lipids 1801(4):438-445.

37. Cheng, L., Han, X., and Shi*, Y. (2009) A Regulatory Role of LPCAT1 in the Synthesis and Remodeling of Inflammatory Lipids, PAF and LPC, in Diabetic Retinopathy. Am. J. Physiol. Endocrinol. Metab. 297(6):E1276-82.

38. Shi*, Y. and Dong Cheng (2009). Beyond Triglycerol Synthesis: The Dynamic Functional Roles of MGAT and DGAT Enzymes in Energy Metabolism. Am. J. Physiol. Endocrinol. Metab. 297(1):E10-8.

39. Cao, J., Shen, W., Chang Z., and Shi*, Y. (2008) ALCAT1 Is a Polyglycerophospholipid Acyltransferase Potently Regulated by Adenine Nucleotides and Thyroid Status. Am. J. Physiol. Endocrinol. Metab. 296(4):E647-53.

40. Li, X., Huang, M., Zheng, H., Wang, Y., Ren, F., Shang, Y., Zhai, Y., Irwin, D.M., Shi, Y., Chen, D., and Chang, Z. (2008). CHIP promotes Runx2 degradation and negatively regulates osteoblast differentiation. J. Cell Biol. 181(6):959-72.

41. Shi*, Y. (2007) Anti-obesity Pharmacotherapy: Current Treatment Options and Future Perspectives. Handbook of Contemporary Neuropharmacology. (David Sibley, et al., eds.) John Wiley & Sons, Inc., Hoboken, NJ. Volume 3: 815-843.

42. Cao, J., Cheng, L., and Shi*, Y. (2007) Catalytic properties of MGAT3, a putative triacylgycerol synthase. J. Lipid Res. 48(3):583-91

43. Van, Q., Liu, J., Lu, B., Feingold, K.R., Shi, Y., Lee, R.M., and Hatch G.M. (2006) Phospholipid scramblase-3 regulates cardiolipin de novo biosynthesis and its resynthesis in growing Hela cells. Biochem. J. 401(1):103-9.

44. Chen, D., Zhang X-Y, and Shi*, Y. (2006) Identification and functional characterization of hCLS1, a human cardiolipin synthase localized in mitochondria. Biochem. J. 398 (2): 169-176.

45. Zhang, S., Yang, Y, and Shi*, Y. (2005) Characterization of human SCD2, an oligomeric desaturase with improved stability and enzyme activity by cross-linking in intact cells. Biochem. J. 388 (1): 135-142.

46. Yang, Y., Cao, J., and Shi*, Y. (2004) Identification and characterization of a gene encoding human LPGAT1, an endoplasmic reticulum-associated lysophosphatidylglycerol acyltransferase. J. Biol. Chem. 279(53):55866-74.

47. Shi*, Y. (2004) Beyond skin color: emerging roles of melanin-concentrating hormone in energy homeostasis and other physiological functions. Peptides 25 (10): 1605-1611.

48. Shi, Y. and Burn, P. (2004) Lipid metabolic enzymes: emerging drug targets for the treatment of obesity. Nat. Rev. Drug Discov. 3 (8): 695-710.

49. Cao, J., Liu, Y., Lockwood, J., Burn, P., and Shi*, Y. (2004) A novel pathway involved in cardiolipin remodeling revealed by functional characterization of a gene encoding ER-associated lysocardiolipin acyltransferase in mouse. J. Biol. Chem. 279(30):31727-34.

50. Gao, X., Hsu, A, Heinz, L., Morin, J., Shi, Y., Shukla, N., Smiley, D., Xu, J. , Zhong, B., and Slieker, L. (2004) Europium-labeled melanin concentrating hormone analogues: novel ligands for measuring binding to both melanin concentrating hormone receptor 1 and 2. Anal. Biochem. 328 (2):187-195.

51. Cao, J., Hawkins, E., Brozinick, J.T., Liu, X., Zhang, H., Burn, P., and Shi*, Y. (2004). A predominant role of acyl-CoA: monoacylglycerol acyltransferase-2 in dietary fat absorption implicated by tissue distribution, subcellular localization, and up-regulation by high fat diet. J. Biol. Chem. 279(18):18878-86.

52. Lockwood, J., Cao, J., Burn, P., and Shi*, Y. (2003). Human intestinal monoacylglycerol acyltransferase: differential features in tissue expression and activity. Am. J. Physiol. Endocrinol. Metab. 285(5):E927-37.

53. Cao, J., Burn, P., and Shi*, Y. (2003) Properties of the mouse intestinal acyl-CoA:monoacylglycerol acyltransferase, MGAT2. J. Biol. Chem. 278(28):25657-63.

54. Shi, Y., Taylor, S.I., Tan, S.L, and Sonenberg, N. (2003). When translation meets metabolism: multiple links to diabetes. Endocr. Rev. 24, 91-101.

55. Cao, J., Lockwood, J., Burn, P., and Shi*, Y. (2003) Cloning and functional characterization of a mouse intestinal acyl-CoA:monoacylglycerol acyltransferase, MGAT2. J. Biol. Chem. 278(16):13860-6.

56. Tan, S.L, Pause, A., Shi, Y., and Sonenberg, N. (2002). Hepatitis C therapeutics: current status and emerging strategies. Nat. Rev. Drug Discov. 1, 867-881.

57. Chen, Y., Hu, H., Hsu, C.-K., Zhang, Q., Bi, C., Asnicar, M., Hsiung, H.M., Fox, N., Slieker, L.J., Yang, D.D., Heiman, M.L., and Shi*, Y. (2002). Targeted disruption of the melanin-concentrating hormone receptor-1 results in hyperphagia and resistance to diet-induced obesity. Endocrinology 143, 2469-2477.

58. Wu, S., Hu, Y., Wang, J-L, Chatterjee, M., Shi, Y., and Kaufman, R.J. (2002) Ultraviolet light inhibits translation through activation of the unfolded protein response kinase PERK in the lumen of the endoplasmic reticulum. J. Biol. Chem. 277, 18077-18083.

59. De la Serna, I., Cujec, T.P., Shi, Y., and Tyler, B.M. (2000). Non-coordinate regulation of 5S rRNA gene and the gene encoding the 5S rRNA-binding ribosomal protein homolog in Neurospora crassa. Mol. & Gen. Genet. 263, 987-994.

60. Shi, Y., Kanaani, J., Menard-Rose, V., Ma, Y.H., Chang, P-Y., Tobin, A., Hanahan, D., Tobin, A., Grodsky, G., and Baekkeskov, S. (2000). Increased expression of glutamic acid decarboxylase and GABA in pancreatic β-cells impairs first phase insulin secretion. Am. J. Physiol. Endocrinol. Metab. 279, E684-E694.

61. Hayes, S.E., Conner, L. J., Stramm, L.E, and Shi*, Y. (1999). Assignment of pancreatic eIF-2α kinase (EIF2AK3) to human chromosome band 2p12 by radiation hybrid mapping and in situ hybridization. Cytogen. & Cell Genet. 86, 327-328.

62. An, J., Zhao, G., Churgay, L.M., Osborne, J.J., Hale, J.E., Becker, G.W., Gold, G., Stramm, L.E., and Shi*, Y. (1999). Threonine Phosphorylations Induced by RX871024 and Insulin Secretagogues in βTC6-F7 Cells. Am. J. Physiol. Endocrinol. Metab. 277, E862-E869.

63. Shi*, Y., An, J., Liang, J, Hayes, S.E., Sandusky, G.E., Stramm, L.E., and Yang, N.N. (1999). Characterization of a mutant pancreatic eIF-2α kinase, PEK, and co-localization with somatostatin in islet δ-Cells. J. Biol. Chem. 274, 5723-5730.

64. Shi*, Y., Vattem, K.M., Sood, R., An, J., Liang, J.D., Stramm, L.E., and Wek, W.C. (1998). Identification and characterization of pancreatic eIF-2α kinase, PEK, involved in translational control. Mol. & Cell. Biol. 18, 7499-7509. (Reviewed in Nature 397:208-209)

65. Bridgett, M., Cetkovic-Cvrlje, M., O’Rourke, R., Shi, Y., Narayanswami, S., Lambert , J., Ramiya, V., Baekkeskov, S., and Leiter, E.H. (1998). Differential protection in two transgenic lines of NOD/Lt mice hyperexpressing the autoantigen GAD65 in pancreatic β-cells. Diabetes 47, 1848-1856.

66. Shi, Y. and Baekkeskov, S. (1995). Posttranslational modifications of the autoantigen glutamic acid decarboxylase, GAD65. Diabetes ed. Baba S. and Kaneko T, Elsevier Press, 111-115.

67. Anstoot, H-J., Sigurdsson, E., Jaffe, M., Shi, Y., Christgau, S., Grobbee, D., Bruining, G. J., Molenaar, J. L., Hofman, A., and Baekkeskov, S. (1994). Value of antibodies to GAD65 combined with islet cell cytoplasmic antibodies for predicting IDDM in a childhood population. Diabetologia 37, 917-924.

68. Kim, J., Namchuk, M., Bugawan, T., Fu, Q., Jaffe, M., Shi, Y., Aanstoot, H-J., Turck, C., Erlich, H., Lennon, V., and Baekkeskov, S. (1994). Higher autoantibody levels and recognition of a linear NH2-terminal epitope in the autoantigen GAD65, distinguish Stiff-Man Syndrome from insulin dependent diabetes mellitus. J. Exp. Med. 180, 595- 606.

69. Shi, Y., Veit, B., and Baekkeskov, S. (1994). Amino acid residues 24-31 but not palmitoylation of cysteines 30 and 45 are required for membrane anchoring of glutamic acid decarboxylase, GAD65. J. Cell Biol. 124, 927-934.

70. Kim, J., Richter, W., Aanstoot, H-J., Shi, Y., Fu, Q., Rajotte, R., Warnock, G., and Baekkeskov, S. (1993). Differential expression of GAD65 and GAD67 in human, rat, and mouse pancreatic islets. Diabetes 42, 1799-1808.

71. Aanstoot, H-J., Michaels, A., Christgau, S., Shi, Y., Kim, J., and Baekkeskov, S. (1993). Stiff-Man syndrome and type-1 diabetes mellitus: similarities and differences in autoimmune reactions. Moter Unit Hyperactivity States, ed. Layzer, R. B. Raven Press, p53-67.

72. Baekkeskov, S., Aanstoot, H-J., Fu, Q., Jaffe, M., Kim, J., Quan, J., Richter, W., and Shi, Y. (1993). The glutamate decarboxylase and 38kD autoantigens in type-1 diabetes: aspects of structure and epitope recognition. Autoimmunity 15, 24-26.

73. Richter, W., Shi, Y., and Baekkeskov, S. (1993). Autoreactive epitopes defined by diabetes-associated monoclonal antibodies are localized in the middle and C- terminal domains of the smaller form of glutamate decarboxylase. Proc. Natl. Acad. Sci. U.S.A. 90, 2832-2836.

74. Shi, Y. G. and Tyler, B. M. (1991). Coordinate expression of ribosomal protein genes in Neurospora crassa and identification of conserved upstream sequences. Nucl. Acids Res. 19, 6511-6517.

75. Shi, Y. G. and Tyler, B. M. (1991). All internal promoter elements of Neurospora crassa 5 S rRNA and tRNA genes, including the A boxes, are functionally gene-specific. J. Biol. Chem. 266, 8015-8019.

76. Shi, Y. G. and Tyler, B. M. (1989). Pyrrolidine, a non-controlled substance, can replace piperidine for the chemical sequencing of DNA. Nucl. Acids Res. 17, 3317.
*The corresponding author